CN110698397A - Tetrabenazine intermediate, and synthesis method, application and intermediate product for synthesis thereof - Google Patents
Tetrabenazine intermediate, and synthesis method, application and intermediate product for synthesis thereof Download PDFInfo
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
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- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
- C07C217/60—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms linked by carbon chains having two carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
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- C07C43/02—Ethers
- C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
- C07C43/205—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring the aromatic ring being a non-condensed ring
- C07C43/2055—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring the aromatic ring being a non-condensed ring containing more than one ether bond
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- C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
- C07C43/23—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing hydroxy or O-metal groups
Abstract
The invention belongs to the field of drug synthesis, and particularly relates to a tetrabenazine intermediate, a synthesis method, application and an intermediate product for synthesis thereof, wherein the synthesis method comprises the following steps: 3, 4-dihydroxy phenethyl alcohol is taken as an initial raw material to carry out a plurality of reactions in sequence; filtering and washing; separating and extracting; and rotary evaporation and concentration to obtain the 6, 7-dimethoxy-3, 4-dihydroisoquinoline. The method has the advantages of cheap and easily obtained raw materials, easy treatment of byproducts, short reaction time, high chemical purity of products, high yield and the like, and is very suitable for large-scale industrial production.
Description
Technical Field
The invention relates to the field of drug synthesis, and particularly relates to a tetrabenazine intermediate, a synthetic method and application thereof, and an intermediate product for synthesis.
Background
Huntington's Disease (HD) is an autosomal dominant gene-induced neurodegenerative disease, the clinical features include progressive involuntary movements, neuropsychiatric disorders and cognitive impairment. There is currently no effective treatment to delay or arrest the progression of the disease. The treatment of HD has mainly focused on symptomatic therapy, with the aim of reducing the impact of the disease on the ability of the individual, mainly improving motor functions, in the hope of obtaining a favourable impact on their quality of life.
Tetrabenazine (TBZ) was first synthesized in 1956 and was first approved by switzerland for the treatment of neurasthenia and schizophrenia, until 1980 TBZ began to be used for the treatment of various motor dysfunctions. Approved by the Food and Drug Administration (FDA) for the treatment of huntington's disease in 2008, the first and only drug in the united states for the treatment of huntington's disease. TBZ is a dopamine receptor blocker, and inhibits the uptake of monoamines such as 5-hydroxytryptamine, dopamine and norepinephrine by reversibly binding to monoamine transporter 2(VMAT2) in the central nervous system, thereby generating pharmacological activity. The TBZ has the characteristics of safety, effectiveness, no delayed dyskinesia and the like, is the main advantage of 6, 7-dimethoxy-3, 4-dihydroisoquinoline for treating Huntington's chorea, is a key intermediate for synthesizing tetrabenazine, and has wide market prospect.
At present, the synthesis process of 6, 7-dimethoxy-3, 4-dihydroisoquinoline at home and abroad mainly comprises the following modes:
(1) journal of the Chemical Society, vol.95, p.1747 mentions the direct preparation of 6, 7-dimethoxy-3, 4-dihydroisoquinoline by reacting 1,2,3, 4-tetrahydropapaverine with concentrated sulfuric acid. The reaction raw material 1,2,3, 4-tetrahydropapaverine is not industrially produced, is difficult to obtain and has high cost, and the yield is about 30-42 percent, so the method is not suitable for batch production.
(2) Heterocycles, vol.55, #8p.1569-1580, prepared 6, 7-dimethoxy-3, 4-dihydroisoquinoline using urotropin and 3, 4-dimethoxyphenethylamine as starting materials. The raw materials of the reaction are not easy to obtain, and the separation of the by-product 6, 7-dimethoxy-2-methyl-3, 4-dihydro-1H-isoquinoline is difficult, so that the purity of the product is only 35 percent, and the product is not suitable for batch production.
Disclosure of Invention
The invention aims to provide a tetrabenazine intermediate, a synthesis method and application thereof, and an intermediate product for synthesis, so as to improve the yield of 6, 7-dimethoxy-3, 4-dihydroisoquinoline.
In order to solve the above technical problems, the present invention provides a method for synthesizing 6, 7-dimethoxy-3, 4-dihydroisoquinoline, comprising: 3, 4-dihydroxy phenethyl alcohol is taken as an initial raw material to carry out a plurality of reactions in sequence; filtering and washing; separating and extracting; and rotary evaporation and concentration to obtain the 6, 7-dimethoxy-3, 4-dihydroisoquinoline.
Further, the reaction formula of the first reaction is as follows:
further, the first reaction comprises: mixing and stirring 3, 4-dihydroxy phenethyl alcohol, anhydrous potassium carbonate and acetone; adding dimethyl sulfate, and continuing stirring; heating and refluxing; distilling to a small volume; and cooling to room temperature to obtain a first product.
Further, the molar ratio of the 3, 4-dihydroxy phenethyl alcohol, anhydrous potassium carbonate and dimethyl sulfate is 1: 3-4: 2-2.5.
Further, the reaction formula of the second reaction is:
further, the second reaction comprises: stirring and uniformly mixing N, N-dimethylformamide and sodium hydride under a dry nitrogen atmosphere, and cooling by using an ice bath; slowly adding ethanethiol; removing the ice bath and continuing stirring; adding the first product under a dry nitrogen atmosphere, and heating and refluxing; and cooling to room temperature to obtain a second product.
Further, the molar ratio of the first product, sodium hydride and ethanethiol is 1: 1.2-1.8: 1-1.5.
Further, the reaction formula of the third reaction is:
further, the third reaction comprises: under nitrogen, uniformly mixing and stirring the second product, toluene and N, N-dimethylformamide, and heating to 30-35 ℃; adding thionyl chloride, and continuing stirring; adding methylamine solution, and cooling to 5 ℃ by using ice bath; keeping the temperature at 0-25 ℃ and continuing stirring to obtain a third product.
Further, the molar ratio of the second product to the toluene to the solution of thionyl chloride to methylamine is 1: 1.5: 1.5-2.5: 2.5-3.5.
Further, the reaction formula of the fourth reaction is:
further, the fourth reaction comprises: mixing and stirring the third product, the Eton reagent and paraformaldehyde at 75-85 ℃ under nitrogen, and cooling to 5 ℃; adding water and keeping the temperature below 25 ℃; adding isopropyl acetate, and cooling to 5 ℃; a 19M NaOH solution was added to adjust the pH to 8-8.5 and the temperature was kept <25 ℃.
Further, the molar ratio of the third product, the eaton reagent and the paraformaldehyde is 1: 1.1-1.5: 1-1.5.
In a second aspect, the present invention also provides a 6, 7-dimethoxy-3, 4-dihydroisoquinoline, having a structural formula:
in a third aspect, the present invention further provides a first product for synthesizing 6, 7-dimethoxy-3, 4-dihydroisoquinoline, wherein the structural formula of the first product is as follows:
in a fourth aspect, the present invention further provides a second product for synthesizing 6, 7-dimethoxy-3, 4-dihydroisoquinoline, wherein the structural formula of the second product is:
in a fifth aspect, the present invention further provides a third product for synthesizing 6, 7-dimethoxy-3, 4-dihydroisoquinoline, wherein the structural formula of the third product is as follows:
in a sixth aspect, the invention also provides application of the 6, 7-dimethoxy-3, 4-dihydroisoquinoline as an intermediate for synthesizing the tetrabenazine.
The synthesis method has the beneficial effects that 3, 4-dihydroxy phenethyl alcohol is used as an initial raw material, 6, 7-dimethoxy-3, 4-dihydroisoquinoline is synthesized through multiple reactions which are carried out in sequence, and the synthesis method has the advantages of cheap and easily-obtained raw materials, easy treatment of byproducts, short reaction time, high product purity, high product yield and the like, and is very suitable for industrial production.
Drawings
The invention is further illustrated with reference to the following figures and examples.
FIG. 1 is a process flow diagram of the synthetic method of the present invention.
Detailed Description
The present invention will now be described in further detail with reference to the accompanying drawings. These drawings are simplified schematic views illustrating only the basic structure of the present invention in a schematic manner, and thus show only the constitution related to the present invention.
Example 1
As shown in fig. 1, this embodiment 1 provides a method for synthesizing 6, 7-dimethoxy-3, 4-dihydroisoquinoline, which comprises the following steps: step S1, carrying out a plurality of reactions in sequence by taking 3, 4-dihydroxy phenethyl alcohol as an initial raw material; step S2, filtering and washing; step S3, separating and extracting; and step S4, rotary evaporation and concentration to obtain the 6, 7-dimethoxy-3, 4-dihydroisoquinoline. Specifically, after multiple reactions, a solid precipitate can be filtered out by using a Buchner funnel, then a filter cake is washed by IPAc, the filtrate mixture is transferred to a separating funnel for separation and extraction, and rotary evaporation and concentration are carried out to obtain yellow oily matter, namely 6, 7-dimethoxy-3, 4-dihydroisoquinoline.
The synthesis method of this example 1 selects 3, 4-dihydroxy phenylethanol as the initial raw material, and synthesizes 6, 7-dimethoxy-3, 4-dihydroisoquinoline through multiple reactions that are performed successively, which has the advantages of cheap and easily available raw materials, easily treated by-products, short reaction time, high product purity, high product yield, and the like, and is very suitable for industrial production.
As an alternative to the first reaction.
The first reaction comprises the following steps: adding 3, 4-dihydroxy phenethyl alcohol, anhydrous potassium carbonate and acetone into a three-neck flask, and starting a stirrer to stir; adding dimethyl sulfate into the mixture within 5 minutes, and continuously stirring for 25-30 minutes; then heating and refluxing for 2 hours; distillation to a small volume (typically 1/10 before distillation for the remaining volume) followed by cooling to room temperature gave the first product.
Specifically, the reaction formula of the first reaction is as follows:
wherein MeO represents methoxy, i.e. CH3O-。
Optionally, the molar ratio of the 3, 4-dihydroxy phenethyl alcohol, anhydrous potassium carbonate and dimethyl sulfate is 1: 3-4: 2-2.5.
As an alternative embodiment of the second reaction.
The second reaction comprises: adding dry N, N-dimethylformamide (anhydrous DMF) and sodium hydride into a three-neck flask provided with a magnetic stirrer, a condenser, a dropping funnel and a nitrogen inlet to obtain a suspension; the suspension was stirred under a dry nitrogen atmosphere and cooled with an ice bath; meanwhile, the ethanethiol is slowly added into the mixture within 20 minutes, the ice bath is removed, and the mixture is continuously stirred for 10 minutes, so that the violent reaction and excessive heat generation are avoided; the first product was poured in, heated to reflux under a dry nitrogen atmosphere for 1.5 hours, and cooled to room temperature to give a second product.
Specifically, the reaction formula of the second reaction is as follows:
optionally, the molar ratio of the first product, sodium hydride and ethanethiol is 1: 1.2-1.8: 1-1.5.
As an alternative embodiment of the third reaction.
The third reaction comprises the following steps: adding anhydrous toluene and anhydrous DMF into the second product under nitrogen, and heating to 30-35 ℃; keeping the internal temperature at less than 40 ℃, adding thionyl chloride through an addition funnel within 30 minutes, and continuing stirring for 0.5 hour to avoid violent reaction and excessive heat generation; adding methylamine solution (40 wt% methylamine water solution), and cooling to 5 deg.C with ice bath; keeping the temperature at 0-25 ℃ and continuing stirring for 0.5-1 hour to obtain a third product.
Specifically, the reaction formula of the third reaction is as follows:
optionally, the molar ratio of the second product to the toluene to the solution of thionyl chloride to methylamine is 1: 1.5: 1.5-2.5: 2.5-3.5.
As an alternative to the fourth reaction.
The fourth reaction comprises: adding an Eton reagent and paraformaldehyde into the third product under nitrogen, controlling the temperature to 75-85 ℃, and stirring for reacting for 2 hours; cooled to 5 ℃ with an ice bath and water was added through the addition funnel over 30 minutes while maintaining the internal temperature <25 ℃; isopropyl acetate (IPAc) was added and the mixture was cooled to 5 ℃ with an ice bath; the pH of the mixture was adjusted to 8-8.5 using 19M (strength) NaOH solution while maintaining the internal temperature at <25 ℃ with an ice bath.
Specifically, the reaction formula of the fourth reaction is as follows:
optionally, the molar ratio of the third product, eaton reagent and paraformaldehyde is 1: 1.1-1.5: 1-1.5.
In addition, substances (such as acetone, N-dimethylformamide, isopropyl acetate, NaOH solution) and the like, the contents of which are not explicitly mentioned in example 1, are generally used as a solvent, a catalyst or a regulator, and can be adjusted according to the contents of the reactants.
Example 2
Based on example 1, this example 2 provides a 6, 7-dimethoxy-3, 4-dihydroisoquinoline, whose structural formula is:
for the contents of the components of 6, 7-dimethoxy-3, 4-dihydroisoquinoline and the specific implementation process, refer to the relevant discussion of example 1, which is not repeated herein.
Example 3
Based on example 1, this example 3 provides a first product for synthesizing 6, 7-dimethoxy-3, 4-dihydroisoquinoline, with the structural formula:
for the contents of the components of the first product and the specific implementation process, refer to the related discussion of example 1, and are not repeated herein.
Example 4
Based on example 1, this example 4 provides a second product for synthesizing 6, 7-dimethoxy-3, 4-dihydroisoquinoline, with the structural formula:
for the contents of the components of the second product and the specific implementation process, refer to the related discussion of example 1, and are not repeated herein.
Example 5
Based on example 1, this example 5 provides a third product for synthesizing 6, 7-dimethoxy-3, 4-dihydroisoquinoline, with the structural formula:
for the contents of the components of the third product and the specific implementation process, refer to the related discussion of example 1, and are not repeated herein.
Example 6
Based on example 1, this example 6 provides the use of 6, 7-dimethoxy-3, 4-dihydroisoquinoline as an intermediate in the synthesis of tetrabenazine.
Optionally, the tetrabenazine is a dopamine receptor blocker, which can inhibit the uptake of monoamines such as 5-hydroxytryptamine, dopamine and norepinephrine by reversibly binding to central nervous system monoamine transporter 2(VMAT2) to generate pharmacological activity for treating Huntington's chorea.
For the contents of the components of 6, 7-dimethoxy-3, 4-dihydroisoquinoline and the specific implementation process, refer to the relevant discussion of example 1, which is not repeated herein.
Example 7
(1) 154.16g of 3, 4-dihydroxyphenylethanol, 414.63g of anhydrous potassium carbonate and 1000ml of acetone are added into a three-neck flask, a stirrer is started, 252.26g of dimethyl sulfate is added into the mixture within 5 minutes, stirring is continued for 25 minutes, then heating and refluxing are carried out for 2 hours, and the mixture is cooled to room temperature after being distilled to a small volume to obtain a first product.
(2) To a three-necked flask equipped with a magnetic stirrer, a condenser, a dropping funnel and a nitrogen inlet was added dry 500ml of DMF (N, N-dimethylformamide) and 28.8g of sodium hydride. The suspension was stirred under a dry nitrogen atmosphere and cooled with an ice bath, while 62.13g of ethanethiol were slowly added thereto over 20 minutes, the ice bath was removed and stirring was continued for 10 minutes. Pouring the first product in the step (1) into the mixture, heating and refluxing for 1.5 hours under a dry nitrogen atmosphere, and cooling to room temperature to obtain a second product.
(3) 138.21g of dry toluene, 500ml of dry DMF were added to the second product in (2) under nitrogen, warmed to 30 ℃, 178.45g of thionyl chloride was added through an addition funnel over 30 minutes at a rate to maintain the internal temperature at <40 ℃, stirring was continued for 0.5 hour, 77.5g of methylamine solution (40 wt% aqueous methylamine solution) was added and cooled to 5 ℃ with an ice bath; the temperature is kept between 0 ℃ and 25 ℃ and stirring is continued for 0.5 hour to obtain a third product.
(4) Adding 261.85g of Eton's reagent, 90g of paraformaldehyde to the third product in (3) under nitrogen, controlling the temperature to 75 ℃, stirring for 2 hours, cooling the reaction mixture to 5 ℃ with an ice bath, and adding 300ml of water through an addition funnel over 30 minutes while maintaining the internal temperature <25 ℃; 500ml of isopropyl acetate (IPAc) were added and the mixture was cooled to 5 ℃ with an ice bath. The pH of the mixture was adjusted to 8-8.5 using 19M NaOH solution while maintaining the internal temperature at <25 ℃ with an ice bath.
(5) Filtering out solid precipitate by using a Buchner funnel, washing a filter cake by using IPAc, transferring a filtrate mixture into a separating funnel for separation and extraction, and concentrating by rotary evaporation to obtain yellow oily matter, namely 6, 7-dimethoxy-3, 4-dihydroisoquinoline. (the obtained product 6, 7-dimethoxy-3, 4-dihydroisoquinoline, with a mass of 170.75g, a purity of 89.227% and a yield of 79.67%).
Example 8
(1) 154.16g of 3, 4-dihydroxyphenylethanol, 483.73g of anhydrous potassium carbonate and 1000ml of acetone are added into a three-neck flask, a stirrer is started, 277.48g of dimethyl sulfate is added into the mixture within 5 minutes, stirring is continued for 28 minutes, then heating and refluxing are carried out for 2 hours, and the mixture is distilled to a small volume and then cooled to room temperature, so as to obtain a first product.
(2) To a three-necked flask equipped with a magnetic stirrer, a condenser, a dropping funnel and a nitrogen inlet was added dry 500ml of DMF (N, N-dimethylformamide) and 36g of sodium hydride. The suspension was stirred under a dry nitrogen atmosphere and cooled with an ice bath, while 74.56g of ethanethiol were slowly added thereto over 20 minutes, the ice bath was removed and stirring was continued for 10 minutes. Pouring the first product in the step (1) into the mixture, heating and refluxing for 1.5 hours under a dry nitrogen atmosphere, and cooling to room temperature to obtain a second product.
(3) 138.21g of dry toluene, 500ml of dry DMF was added to the second product in (2) under nitrogen, warmed to 32 ℃, 237.94gg of thionyl chloride was added through an addition funnel over 30 minutes at a rate to maintain the internal temperature at <40 ℃, stirring was continued for 0.5 hours, 93g of methylamine solution (40 wt% aqueous solution) was added and cooled to 5 ℃ with an ice bath; the temperature is maintained at 0-25 ℃ and stirring is continued for 1 hour to obtain a third product.
(4) Adding 309.47g of Eton's reagent, 108g of paraformaldehyde to the third product in (3) under nitrogen, controlling the temperature to 80 ℃ and stirring for 2 hours, cooling the reaction mixture to 5 ℃ with an ice bath, and adding 300ml of water through an addition funnel over 30 minutes while maintaining the internal temperature <25 ℃; 500ml of isopropyl acetate (IPAc) were added and the mixture was cooled to 5 ℃ with an ice bath. The pH of the mixture was adjusted to 8-8.5 using 19M NaOH solution while maintaining the internal temperature at <25 ℃ with an ice bath.
(5) Filtering out solid precipitate by using a Buchner funnel, washing a filter cake by using IPAc, transferring a filtrate mixture into a separating funnel for separation and extraction, and concentrating by rotary evaporation to obtain yellow oily matter, namely 6, 7-dimethoxy-3, 4-dihydroisoquinoline. (the obtained product 6, 7-dimethoxy-3, 4-dihydroisoquinoline, with a mass of 174.17g, a purity of 89.756% and a yield of 81.75%).
Example 9
(1) 154.16g of 3, 4-dihydroxyphenylethanol, 552.84g of anhydrous potassium carbonate and 1000ml of acetone are added into a three-neck flask, a stirrer is started, 315.32g of dimethyl sulfate is added into the mixture within 5 minutes, stirring is continued for 30 minutes, then heating and refluxing are carried out for 2 hours, and the mixture is cooled to room temperature after being distilled to a small volume to obtain a first product.
(2) To a three-necked flask equipped with a magnetic stirrer, a condenser, a dropping funnel and a nitrogen inlet were added dry 500ml of DMF (N, N-dimethylformamide) and 43.2g of sodium hydride. The suspension was stirred under a dry nitrogen atmosphere and cooled with an ice bath, while 93.2g of ethanethiol were slowly added thereto over 20 minutes, the ice bath was removed and stirring was continued for 10 minutes. Pouring the first product in the step (1) into the mixture, heating and refluxing for 1.5 hours under a dry nitrogen atmosphere, and cooling to room temperature to obtain a second product.
(3) 138.21g of dry toluene, 500ml of dry DMF were added to the second product in (2) under nitrogen, warmed to 35 ℃, 297.43g of thionyl chloride was added through an addition funnel over 30 minutes at a rate to maintain the internal temperature at <40 ℃, stirring was continued for 0.5 hour, 108.5g of methylamine solution (40 wt% aqueous solution) was added and cooled to 5 ℃ with an ice bath; the temperature is maintained at 0-25 ℃ and stirring is continued for 1 hour to obtain a third product.
(4) Adding 357.08g of Eton's reagent, 135g of paraformaldehyde to the third product in (3) under nitrogen, controlling the temperature to 85 ℃, stirring for 2 hours, cooling the reaction mixture to 5 ℃ with an ice bath, and adding 300ml of water through an addition funnel over 30 minutes while maintaining the internal temperature <25 ℃; 500ml of isopropyl acetate (IPAc) were added and the mixture was cooled to 5 ℃ with an ice bath.
(5) The pH of the mixture was adjusted to 8-8.5 using 19M NaOH solution while maintaining the internal temperature at <25 ℃ with an ice bath. Filtering out solid precipitate by using a Buchner funnel, washing a filter cake by using IPAc, transferring a filtrate mixture into a separating funnel for separation and extraction, and concentrating by rotary evaporation to obtain yellow oily matter, namely 6, 7-dimethoxy-3, 4-dihydroisoquinoline. (the obtained product 6, 7-dimethoxy-3, 4-dihydroisoquinoline has the mass of 178.79g, the purity of 90.090 percent and the yield of 84.23 percent).
Example 10
This example 10 was conducted to investigate the influence of the purity and yield of 6, 7-dimethoxy-3, 4-dihydroisoquinoline synthesized in examples 7 to 9, as shown in Table 1. In the process of synthesizing the 6, 7-dimethoxy-3, 4-dihydroisoquinoline, the content of anhydrous potassium carbonate, dimethyl sulfate, sodium hydride, ethanethiol, an Eton reagent, paraformaldehyde and the like is improved, so that multiple reactions which are carried out successively can be fully carried out, the yield of each intermediate product (a first product, a second product and a third product) is improved, and the 6, 7-dimethoxy-3, 4-dihydroisoquinoline is ensured to have higher purity and yield.
TABLE 1 component content, product yield and purity
In conclusion, the tetrabenazine intermediate, the synthesis method, the application and the intermediate product for synthesis of the tetrabenazine intermediate adopt 3, 4-dihydroxyphenylethanol as an initial raw material, and are combined with the subsequently added reactants to perform a plurality of reactions in sequence to finally synthesize the 6, 7-dimethoxy-3, 4-dihydroisoquinoline, and the reaction rate can be effectively improved and the reaction time can be shortened by controlling the reaction conditions (such as reaction nitrogen atmosphere, reaction solvent, reactant adding speed, reaction temperature, solution PH value and the like) of each reaction; by reasonably setting the component content proportion of each raw material, the purity and yield of the product can be effectively improved. Therefore, the synthesis method has the advantages of cheap and easily-obtained raw materials, easy treatment of byproducts, short reaction time, high chemical purity of the product, high yield and the like, particularly the chemical purity of the product can reach more than 90.09%, and the yield can reach more than 84.23%, so that the method is very suitable for large-scale industrial production. In addition, the high-purity 6, 7-dimethoxy-3, 4-dihydroisoquinoline is more suitable to be used as an important intermediate for synthesizing the tetrabenazine, and can reduce ineffective components in the medicament, thereby improving the medicament effect.
In light of the foregoing description of the preferred embodiment of the present invention, many modifications and variations will be apparent to those skilled in the art without departing from the spirit and scope of the invention. The technical scope of the present invention is not limited to the content of the specification, and must be determined according to the scope of the claims.
Claims (18)
1. A synthetic method of 6, 7-dimethoxy-3, 4-dihydroisoquinoline is characterized by comprising the following steps:
3, 4-dihydroxy phenethyl alcohol is taken as an initial raw material to carry out a plurality of reactions in sequence;
filtering and washing;
separating and extracting; and
rotary evaporation and concentration to obtain the 6, 7-dimethoxy-3, 4-dihydroisoquinoline.
2. The method of synthesis according to claim 1,
the reaction formula of the first reaction is as follows:
3. the method of synthesis according to claim 1,
the first reaction comprises the following steps:
mixing and stirring 3, 4-dihydroxy phenethyl alcohol, anhydrous potassium carbonate and acetone;
adding dimethyl sulfate, and continuing stirring;
heating and refluxing;
distilling to a small volume; and
cooling to room temperature to obtain the first product.
4. The method of synthesis according to claim 3,
the molar ratio of the 3, 4-dihydroxy phenethyl alcohol, the anhydrous potassium carbonate and the dimethyl sulfate is 1: 3-4: 2-2.5.
5. The method of synthesis according to claim 1,
the reaction formula of the second reaction is as follows:
6. the method of synthesis according to claim 3,
the second reaction comprises the following steps:
stirring and uniformly mixing N, N-dimethylformamide and sodium hydride under a dry nitrogen atmosphere, and cooling by using an ice bath;
slowly adding ethanethiol;
removing the ice bath and continuing stirring;
adding the first product under a dry nitrogen atmosphere, and heating and refluxing; and
cooling to room temperature to obtain a second product.
7. The method of synthesis according to claim 6,
the molar ratio of the first product to the sodium hydride to the ethanethiol is 1: 1.2-1.8: 1-1.5.
8. The method of synthesis according to claim 1,
the reaction formula of the third reaction is as follows:
9. the method of synthesis according to claim 6,
the third reaction comprises:
under nitrogen, uniformly mixing and stirring the second product, toluene and N, N-dimethylformamide, and heating to 30-35 ℃;
adding thionyl chloride, and continuing stirring;
adding methylamine solution, and cooling to 5 ℃ by using ice bath;
keeping the temperature at 0-25 ℃ and continuing stirring to obtain a third product.
10. The method of synthesis according to claim 9,
the molar ratio of the second product to the toluene to the solution of thionyl chloride to methylamine is 1: 1.5: 1.5-2.5: 2.5-3.5.
11. The method of synthesis according to claim 1,
the reaction formula of the fourth reaction is:
12. the method of synthesis according to claim 9,
the fourth reaction comprises:
mixing and stirring the third product, the Eton reagent and paraformaldehyde at 75-85 ℃ under nitrogen, and cooling to 5 ℃;
adding water and keeping the temperature below 25 ℃;
adding isopropyl acetate, and cooling to 5 ℃;
a 19M NaOH solution was added to adjust the pH to 8-8.5 and the temperature was kept <25 ℃.
13. The method of synthesis according to claim 12,
the molar ratio of the third product to the Eton reagent to the paraformaldehyde is 1: 1.1-1.5: 1-1.5.
14. A6, 7-dimethoxy-3, 4-dihydroisoquinoline is characterized in that,
the structural formula of the 6, 7-dimethoxy-3, 4-dihydroisoquinoline is as follows:
15. a first product for synthesizing 6, 7-dimethoxy-3, 4-dihydroisoquinoline is characterized in that,
the first product has the structural formula:
16. a second product for synthesizing 6, 7-dimethoxy-3, 4-dihydroisoquinoline, which is characterized in that,
the structural formula of the second product is:
17. a third product for synthesizing 6, 7-dimethoxy-3, 4-dihydroisoquinoline, which is characterized in that,
the structural formula of the third product is:
18. application of 6, 7-dimethoxy-3, 4-dihydroisoquinoline as intermediate for synthesizing tetrabenazine.
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| CN102060765A (en) * | 2010-12-24 | 2011-05-18 | 中国药科大学 | Tetrahydroisoquinoline derivative, preparation method and application thereof |
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| WO2012081031A1 (en) * | 2010-12-15 | 2012-06-21 | Enaltec Labs Pvt. Ltd. | Process for preparing tetrabenazine |
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