CN113735799A - Synthetic method of dyclonine hydrochloride - Google Patents
Synthetic method of dyclonine hydrochloride Download PDFInfo
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- CN113735799A CN113735799A CN202010473380.6A CN202010473380A CN113735799A CN 113735799 A CN113735799 A CN 113735799A CN 202010473380 A CN202010473380 A CN 202010473380A CN 113735799 A CN113735799 A CN 113735799A
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- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/10—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
- C07D295/104—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/108—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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Abstract
The invention discloses a novel synthesis method of dyclonine hydrochloride. The method takes bromoacetophenone as a starting material, and produces dyclonine hydrochloride through Mannich reaction and C-O crosslinking reaction. Compared with the prior art, the method has the advantages of easily obtained starting materials, controllable reaction temperature, higher purity, shortened time, improved yield and the like, avoids the use of high-toxicity reagents such as acetyl chloride, 3-chloropropionyl chloride and the like, and is more favorable for medicine safety and industrialized mass production.
Description
Technical Field
The invention relates to the technical field of drug synthesis, in particular to a method for synthesizing dyclonine hydrochloride.
Background
Dyclonine hydrochloride (english name Dyclonine hydrochloride); the chemical name is 4-butoxy-beta-piperidyl propiophenone hydrochloride, and the structural formula is as follows:
dyclonine hydrochloride is a compound with local anesthetic action, can block the conduction of various nerve impulses or stimulations, inhibit touch sense and pain sense, and has the functions of relieving pain, relieving itching and sterilizing on the skin. The product was first developed in 1932 by Sharp & Dohme in the united states, and there have been few reports of dyclonine abroad until the 21 st century.
1993 indian patent IN172270A reported a synthetic route to dyclonine hydrochloride, which was as follows:
the yield of butoxyacetophenone in this route is low (up to 75%), affecting the overall yield; in addition, in the route, in an isopropanol solution of HCl, process steps are added, the amount of three wastes in post-treatment is high, and the production cost of the raw material medicine is increased.
IN 2009, a patent of Yangzjiang pharmaceutical industry group CN200810087761.X discloses and reports a new method for synthesizing dyclonine hydrochloride, which is improved on the basis of a patent IN172270A document, and the specific route is as follows:
although the process improves the reported synthesis process, the technical problems of long acylation reaction time, high toxicity of the used anhydride, long-time high-temperature distillation during the purification of the butyl benzene and the p-butoxyacetophenone, low yield and the like still exist.
2017, Guizhou Shenqi pharmaceutical industry patent CN201710475386.5 discloses another method for synthesizing dyclonine hydrochloride, and the specific route is as follows:
the method is further improved in a route reported in a patent CN200810087761.X, and 3-chloropropionyl chloride is mainly used, is inflammable, can react violently when meeting water, and has harsh storage conditions and potential safety hazards.
Similarly, in 2017, a daclonine hydrochloride method patent CN201710438702.1 is disclosed in Tianhua pharmacy, which is a Changzhou city, and the specific synthetic route is as follows:
the method shortens the route disclosed by the patent CN200810087761.X, the starting materials of p-hydroxyacetophenone and bromobutane are expensive, the reaction is two-phase reaction, the reaction is difficult, and a phase transfer catalyst needs to be added.
Disclosure of Invention
Aiming at the defects of the prior art, the technical problem to be solved by the invention is to provide a novel method for synthesizing dyclonine hydrochloride.
The technical scheme of the invention is as follows:
a synthetic method of dyclonine hydrochloride comprises the following synthetic route:
wherein X is F, Cl, Br or I; n is 3 to 100;
the synthesis method comprises the following steps:
1) in the presence of an organic solvent, carrying out Mannich reaction on the compound I, piperidine hydrochloride and paraformaldehyde to obtain a compound II;
2) under the protection of nitrogen and the presence of a ligand and under the action of a catalyst, carrying out C-O crosslinking reaction on the compound II and n-butyl alcohol to obtain a compound III, namely dyclonine hydrochloride.
Preferably, the first and second electrodes are formed of a metal,
in the step 1) described above, the step of,
a compound I: piperidine hydrochloride salt: the molar ratio of paraformaldehyde is 1: 1.2-1.8: 3.0 to 4.0 parts by weight,
the reaction temperature is 50-95 ℃; the reaction time is 3-7 h;
the organic solvent is any one of ethanol, isopropanol and acetic acid.
Preferably, the first and second electrodes are formed of a metal,
in the step 1), X is Br; n is 3.
In the step 2) described above, the step of,
compound ii: the mol ratio of n-butanol is 1: 5.0 to 10.0;
the reaction temperature is 60-120 ℃; the reaction time is 5-15 h;
the ligand is any one of phenanthroline and derivatives, acetylacetone and trans-4-hydroxy-L-proline;
the catalyst is any one of cuprous iodide, copper powder and metal palladium.
More preferably still, the first and second liquid crystal compositions are,
in the step 1) described above, the step of,
the compound I is p-bromoacetophenone; a compound I: piperidine hydrochloride salt: the molar ratio of paraformaldehyde is 1: 1.2: 3.0;
the reaction condition is that the reaction is carried out for 4 hours at 60 ℃;
the organic solvent is preferably ethanol.
In the step 2) described above, the step of,
the compound II is 4-bromo-beta-piperidyl propiophenone hydrochloride; compound ii: the mol ratio of n-butanol is 1: 5;
the reaction condition is that the reaction is carried out for 7 hours at 80 ℃;
the ligand used is preferably trans-4-hydroxy-L-proline;
the catalyst used is preferably cuprous iodide.
In the step 1), the compound I is obtained by reacting halogenated benzene with acetyl chloride, wherein the halogenated benzene is any one of fluorobenzene, chlorobenzene, bromobenzene and iodobenzene. The halogenated benzene is preferably bromobenzene.
The preferred technical route of the invention takes the p-bromoacetophenone as the starting material, and comprises the following steps: p-bromoacetophenone, piperidine hydrochloride and paraformaldehyde react with ethanol as a solvent to generate 4-bromo-beta-piperidyl propiophenone hydrochloride; the second step is that: and (3) reacting the obtained product with n-butyl alcohol under the catalysis of CuI to obtain the final product dyclonine hydrochloride.
The invention has the following technical effects:
1) compared with the prior art, the method has the advantages of easily obtained starting materials, controllable reaction temperature, higher purity, shortened time, improved yield and the like, avoids the use of high-toxicity reagents such as acetyl chloride, 3-chloropropionyl chloride and the like, and is more favorable for drug safety and industrial mass production because all the used dissolving reagents in the process are low in toxicity.
2) By preferably using cuprous iodide as a catalyst and trans-4-hydroxy-L-proline as a ligand, the forward progress of the reaction is promoted and the reaction yield is increased.
3) Less three wastes and more environment-friendly.
Drawings
FIG. 1 is an HPLC chromatogram of the product obtained in example 1.
FIG. 2 is an MS spectrum of the product obtained in example 1.
FIG. 3 is an H-NMR spectrum of the product obtained in example 1.
Detailed Description
Paraformaldehyde used in the following examples and comparative examples was obtained from national pharmaceutical group chemical Co., Ltd, product No. 80096618, CAS: 30525-89-4.
EXAMPLE 1 preparation of dyclonine hydrochloride
(1) Preparation of 4-bromo- β -piperidinyl propiophenone hydrochloride: 19.9g of bromoacetophenone, 100mL of ethanol, 14.6g of piperidine hydrochloride (1.2eq), 8.9g of paraformaldehyde (3.0eq) and 2mL of hydrochloric acid are added into a 250mL three-neck flask, the mixture is stirred, heated to 60 ℃ and reacted for 4 hours, heating is stopped, cooling and crystallization are carried out for 4 hours at 0 ℃, suction filtration is carried out, filter cakes are rinsed by isopropanol, and vacuum drying is carried out at 60 ℃ to obtain 30.6kg of white solid, the HPLC purity is 97%, and the yield is 92%.
(2) Preparation of dyclonine hydrochloride: under nitrogen protection, 183mL of dimethyl sulfoxide, 16.6g of 4-bromo-. beta. -piperidyl propiophenone hydrochloride, 1.9g of cuprous iodide (0.2eq), 2.6g of trans-4-hydroxy-L-proline (0.4eq), 13.8g of potassium carbonate (2.0eq), 3.1g of tetrabutylammonium bromide (0.19eq) and 33mL of acetonitrile were charged into a 500mL three-necked flask, and the internal temperature of the flask was controlled at 50 ℃. 18.5g of n-butanol (5.0eq) was added rapidly, and the temperature in the autoclave was controlled at 80 ℃ and held for 7 hours. After the reaction is finished, quenching with ice water, adding dichloromethane, filtering, layering, washing the organic phase twice with water, concentrating the organic phase by half volume, adding ethyl acetate, crystallizing, and filtering. The obtained filter cake was refined once with ethanol. After drying at 50 ℃ for 6h in vacuo, 13.2g of a white solid powder was obtained with an HPLC purity of 99.9%, yield 81%, mp: 173 ℃.
From the above results, it can be seen that: in the reaction system of step 2) of this example, cuprous iodide is used as a catalyst, and trans-4-hydroxy-L-proline as a ligand is used, so that the reaction yield is high.
Example 2 preparation of dyclonine hydrochloride
(1) Preparation of 4-bromo- β -piperidinyl propiophenone hydrochloride: 19.9g of bromoacetophenone, 100mL of isopropanol, 14.6g of piperidine hydrochloride (1.2eq), 8.9g of paraformaldehyde (3.0eq) and 2mL of hydrochloric acid are added into a 250mL three-neck flask, the mixture is stirred, heated to 60 ℃ and reacted for 4 hours, heating is stopped, cooling and crystallization are carried out for 4 hours at 0 ℃, suction filtration is carried out, a filter cake is rinsed by isopropanol, and vacuum drying is carried out at 60 ℃ to obtain 27.9kg of white solid, the HPLC purity is 90%, and the yield is 84%.
(2) Preparation of dyclonine hydrochloride: the reaction conditions were kept the same as in example 1, and 12.5g of a white solid powder was obtained with a purity of 99.2% and a yield of 77%.
From the above results, it can be seen that: in the reaction system of step 2) of this example, cuprous iodide is used as a catalyst, and trans-4-hydroxy-L-proline as a ligand is used, so that the reaction yield is high.
Control example 1 preparation of dyclonine hydrochloride
(1) Preparation of 4-bromo- β -piperidinyl propiophenone hydrochloride: the reaction conditions were kept the same as in example 1.
(2) Preparation of dyclonine hydrochloride: under the protection of nitrogen, 183mL of dimethyl sulfoxide, 16.6g of 4-bromo- β -piperidyl propiophenone hydrochloride, 2.6g of trans-4-hydroxy-L-proline (0.4eq), 13.8g of potassium carbonate (2.0eq), 3.1g of tetrabutylammonium bromide (0.19eq) and 33mL of acetonitrile were added to a 500mL three-necked flask, and the internal temperature of the flask was controlled to 50 ℃. 18.5g of n-butanol (5.0eq) was added rapidly, and the temperature in the autoclave was controlled at 80 ℃ and held for 7 hours. And detecting that no product is generated.
From the above results, it can be seen that: in the reaction system of step 2) of this comparative example, the dyclonine hydrochloride product was not successfully obtained by using only the ligand trans-4-hydroxy-L-proline without using a catalyst.
Control example 2 preparation of dyclonine hydrochloride
(1) Preparation of 4-bromo- β -piperidinyl propiophenone hydrochloride: the reaction conditions were kept the same as in example 1.
(2) Preparation of dyclonine hydrochloride: under the protection of nitrogen, 183mL of dimethyl sulfoxide, 16.6g of 4-bromo-. beta. -piperidyl propiophenone hydrochloride, 3.6g of 1, 10-phenanthroline (0.4eq), 13.8g of potassium carbonate (2.0eq), 3.1g of tetrabutylammonium bromide (0.19eq), and 33mL of acetonitrile were charged in a 500mL three-necked flask, and the internal temperature of the flask was controlled to 50 ℃. 18.5g of n-butanol (5.0eq) was added rapidly, and the temperature in the autoclave was controlled at 80 ℃ and held for 7 hours. After the reaction is finished, quenching with ice water, adding dichloromethane, filtering, layering, washing the organic phase twice with water, concentrating the organic phase by half volume, adding ethyl acetate, crystallizing, and filtering. The obtained filter cake was refined once with ethanol. After drying at 50 ℃ for 6h under vacuum, 11.1g of white solid powder was obtained with a purity of 99.5% and a yield of 68%.
From the above results, it can be seen that: in the reaction system of step 2) of this comparative example, only the ligand 1, 10-phenanthroline was used without using a catalyst, and although the dyclonine hydrochloride product could be obtained, the yield was significantly lower than that of the reaction system using both a catalyst and a ligand.
EXAMPLE 3 confirmation of Structure (Using the sample obtained in example 1)
(1) Hydrogen nuclear magnetic resonance (1H-NMR)
The instrument model is as follows: deutero chloroform of BRUKER AV-400 nuclear magnetic resonance spectrometer is used as a solvent.
1H-NMR(CDCl3，400MHz)δ12.3(s，1H，H-Cl)，8.0(d，2H，Ar-H)，6.9(d，2H，Ar-H)，4.0(t，2H，CH2)，3.7(t，2H，CH2)，3.5(m，2H，CH2)，3.4(m，2H，CH2)，2.7(s，2H，CH2)，2.2(m，2H，CH2)，1.9-1.0(m，8H，4×CH2)，1.0(m，3H，CH3)
(2) Mass spectrum (ESI, model: Agilent 1260-
The molecular weight of dyclonine hydrochloride is 325.9, wherein the molecular weight of free base is 289.4, the reference is M, and a molecular ion peak (M +1) appears in a mass spectrogram+290.8, corresponding to the molecular weight of dyclonine hydrochloride free base.
(3) HPLC purity 99.9%, determined using HPLC area normalization method, i.e.: column C18 (4.6 mm. times.250 mm,5 μm); the detection wavelength is 282 nm; the column temperature is 40 ℃; flow rate: 1.0ul/min, mobile phase A is 10mmol/L ammonium acetate water solution, mobile phase B: 100% acetonitrile.
Gradient elution for 70 min:
the products of example 2 and control 2 were identical to example 1, confirmed by dot plate control.
Although the embodiments disclosed in the present application are described above, the descriptions are only for the convenience of understanding the present application, and are not intended to limit the present application. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the disclosure as defined by the appended claims.
Claims (7)
1. The method for synthesizing dyclonine hydrochloride is characterized in that the synthetic route is as follows:
wherein X is F, Cl, Br or I; n is 3 to 100;
the synthesis method comprises the following steps:
1) in the presence of an organic solvent, carrying out Mannich reaction on the compound I, piperidine hydrochloride and paraformaldehyde to obtain a compound II;
2) under the protection of nitrogen and the presence of a ligand and under the action of a catalyst, carrying out C-O crosslinking reaction on the compound II and n-butyl alcohol to obtain a compound III, namely dyclonine hydrochloride.
2. The method for synthesizing dyclonine hydrochloride according to claim 1, wherein in the step 1),
a compound I: piperidine hydrochloride salt: the molar ratio of paraformaldehyde is 1: 1.2-1.8: 3.0 to 4.0 parts by weight,
the reaction temperature is 50-95 ℃; the reaction time is 3-7 h;
the organic solvent is any one of ethanol, isopropanol and acetic acid.
3. The method for synthesizing dyclonine hydrochloride according to claim 1, wherein in the step 2),
compound ii: the mol ratio of n-butanol is 1: 5.0 to 10.0;
the reaction temperature is 60-120 ℃; the reaction time is 5-15 h;
the ligand is any one of phenanthroline and derivatives, acetylacetone and trans-4-hydroxy-L-proline;
the catalyst is any one of cuprous iodide, copper powder and metal palladium.
4. The method for synthesizing dyclonine hydrochloride according to claim 1 or 2, wherein in the step 1),
the compound I is p-bromoacetophenone; a compound I: piperidine hydrochloride salt: the molar ratio of paraformaldehyde is 1: 1.2: 3.0;
the reaction condition is that the reaction is carried out for 4 hours at 60 ℃;
the organic solvent is preferably ethanol.
5. The method for synthesizing dyclonine hydrochloride according to claim 1 or 3, wherein in the step 2),
the compound II is 4-bromo-beta-piperidyl propiophenone hydrochloride; compound ii: the mol ratio of n-butanol is 1: 5;
the reaction condition is that the reaction is carried out for 7 hours at 80 ℃;
the ligand used is preferably trans-4-hydroxy-L-proline;
the catalyst used is preferably cuprous iodide.
6. The method for synthesizing dyclonine hydrochloride according to claim 1, wherein in the step 1), the compound I is obtained by reacting halogenated benzene with acetyl chloride, and the halogenated benzene is any one of fluorobenzene, chlorobenzene, bromobenzene and iodobenzene.
7. The method for synthesizing dyclonine hydrochloride according to claim 6, wherein in the step 1), the halogenated benzene is bromobenzene.
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| CN107235930A (en) * | 2017-06-12 | 2017-10-10 | 常州市天华制药有限公司 | A kind of synthetic method of dyclonine hydrochloride |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN117986204A (en) * | 2024-04-02 | 2024-05-07 | 华泰民康(沈阳)科技有限公司 | Synthesis method of dyclonine hydrochloride |
| CN117986204B (en) * | 2024-04-02 | 2024-06-04 | 华泰民康(沈阳)科技有限公司 | Synthesis method of dyclonine hydrochloride |
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