CN114524767B - Synthesis method of sitaxel intermediate 5,7-dichloro-1,2,3,4-tetrahydroisoquinoline hydrochloride - Google Patents
Synthesis method of sitaxel intermediate 5,7-dichloro-1,2,3,4-tetrahydroisoquinoline hydrochloride Download PDFInfo
- Publication number
- CN114524767B CN114524767B CN202210254550.0A CN202210254550A CN114524767B CN 114524767 B CN114524767 B CN 114524767B CN 202210254550 A CN202210254550 A CN 202210254550A CN 114524767 B CN114524767 B CN 114524767B
- Authority
- CN
- China
- Prior art keywords
- compound
- dichloro
- synthesis method
- reaction
- tetrahydroisoquinoline hydrochloride
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention relates to the technical field of drug synthesis, and discloses a synthesis method of a sitaxel intermediate 5,7-dichloro-1,2,3,4-tetrahydroisoquinoline hydrochloride, which comprises the following steps: after hydrogen is extracted from the compound 1 by n-butyl lithium, the compound reacts with iodine to obtain a compound 2; condensing the compound 2 with a condensing agent to obtain an intermediate state; then condensing with methyl methoxy amine hydrochloride in the presence of organic alkali to obtain a compound 3; reducing the compound 3 to obtain a compound 4; in the first stage, a compound 4 is catalyzed by a first catalyst in the presence of alkali and is coupled with trimethylsilyl acetylene; in the second stage, the second catalyst is used for catalyzing, and the second catalyst reacts with ammonia water to close a ring to obtain a compound 5; and reducing the compound 5 by a reducing agent, and acidifying by an acidifying agent to obtain a compound 6. The synthesis method has the advantages of low price and easy obtainment of used raw materials, mild reaction conditions, no use of high-risk reaction, simple requirement on used equipment, high yield and lower total cost, and is suitable for large-scale industrial production.
Description
Technical Field
The invention relates to the technical field of drug synthesis, in particular to a synthesis method of a sitaxel intermediate 5,7-dichloro-1,2,3,4-tetrahydroisoquinoline hydrochloride.
Background
Dry eye, also known as keratoconjunctivitis sicca, is a multifactorial tear and ocular surface disease that can lead to symptoms such as ocular discomfort, visual impairment, and tear film instability, with concomitant increases in tear film permeability and ocular surface inflammation. Dry eye is a chronic, and often progressive, disorder. Depending on the cause and severity, dry eye sometimes does not heal completely. In most cases, however, disease management of dry eye can be successful, and by administering appropriate treatment, eye comfort can be significantly improved, dry eye symptoms can be alleviated, and sometimes even clearer vision can be achieved.
Ritatest (Lifitegrast) was a former research by Shire pharmaceutical company, uk, for the treatment of signs and symptoms of dry eye, with trade names: xiidra. The eye drops of Lifitestast approved by Shire corporation in 2016, 7, 11 days in the United states by FDA are the first new drug approved by FDA for treating dry eye, and are used 2 times a day, about 12 hours apart.
The sitagliptin consists of three fragments, wherein one key fragment is 5,7-dichloro-1,2,3,4-tetrahydroisoquinoline hydrochloride, the structural formula is shown as the following,
so far, the literature reports 5,7-dichloro-1,2,3,4-tetrahydroisoquinoline hydrochloride synthesis methods mainly have the following types:
the first method is to take 3,5-dichlorobenzaldehyde as raw material, condense with 2-chloroethylamine hydrochloride, reduce by sodium cyanoborohydride, and then obtain 5,7-dichloro-1,2,3,4-tetrahydroisoquinoline by ring closure in the presence of aluminum trichloride (the technical route is shown as follows). Although the reaction process is simple, the reaction temperature of the second step is as high as 185 ℃, common equipment cannot be used, only special high-temperature kettles can be used, and the method is not suitable for scale-up production (ACS Medicinal Chemistry Letters 2012,3 (3), 203-206).
In the second method, 2,4-dichlorobenzyl cyanide is used as a raw material, and is hydrogenated by nickel catalysis to obtain 2,4-dichlorophenethylamine, and then acetic anhydride is used for acetylation, and the raw material and paraformaldehyde are subjected to ring closure in the presence of sulfuric acid and acetic acid to obtain 5,7-dichlorotetrahydroisoquinoline protected by acetyl, and finally 5,7-dichloro-1,2,3,4-tetrahydroisoquinoline is obtained by hydrochloric acid hydrolysis (the technical route is shown as follows). The scheme has a problem that the first step hydrogenation reduction cyano reaction belongs to high-risk reaction, safety accidents are easy to occur, and the production has higher safety risk (the patent publication number is CN 111057003A).
In the third method, 3,5-dichlorobenzaldehyde is used as a raw material, condensed with 2-aminoacetaldehyde dimethyl acetal to obtain Xi Fujian, subjected to ring closure in sulfuric acid to obtain 5,7-dichloroisoquinoline, and then hydrogenated by platinum dioxide to obtain 5,7-dichloro-1,2,3,4-tetrahydroisoquinoline (the technical route is shown as follows). The problem with this route is that the second step reaction temperature is 140 ℃, the temperature is relatively high, scale-up production is not required, and the reaction solvent is concentrated sulfuric acid, which is very dangerous at high temperatures. The third step is that the hydrogenation reaction belongs to high-risk reaction and has larger potential safety hazard (Journal of Medicinal Chemistry 1980,23 (5), 506-511).
In summary, the present method for synthesizing 5,7-dichloro-1,2,3,4-tetrahydroisoquinoline hydrochloride has certain limitations, and the safety risk of mass production is high.
Disclosure of Invention
< problems to be solved by the present invention >
The existing 5,7-dichloro-1,2,3,4-tetrahydroisoquinoline hydrochloride synthesis method is not suitable for large-scale production and has the problem of safety risk in production.
< technical solution adopted in the present invention >
Aiming at the technical problems, the invention aims to provide a synthesis method of a sitaxel intermediate 5,7-dichloro-1,2,3,4-tetrahydroisoquinoline hydrochloride, the synthesis method has the advantages of easily obtained raw materials, no high-risk reaction, mild conditions and higher yield, and is suitable for industrial production.
The specific contents are as follows:
the synthesis process of preparing lipostat intermediate 5,7-dichloro-1,2,3,4-tetrahydro isoquinoline hydrochloride includes the following steps:
(1) Iodination reaction: after hydrogen is extracted from the compound 1 by n-butyl lithium, the compound reacts with iodine to obtain a compound 2;
(2) Amidation reaction: condensing the compound 2 with a condensing agent to obtain an intermediate state; then condensing with methyl methoxy amine hydrochloride in the presence of organic alkali to obtain a compound 3;
(3) Reduction reaction: reducing the compound 3 with a reducing agent to obtain a compound 4;
(4) Coupling reaction: in the first stage, a compound 4 is catalyzed by a first catalyst in the presence of alkali and is coupled with trimethylsilyl acetylene; in the second stage, the second catalyst is used for catalyzing, and the second catalyst reacts with ammonia water to close the ring to obtain a compound 5;
(5) Reduction reaction: the compound 5 is reduced by a reducing agent in the presence of Lewis acid, and is acidified by an acidifying agent to obtain a compound 6.
< technical mechanism adopted in the present invention >
By adopting a Sonogashira reaction, alkynyl is introduced on a benzene ring under the action of a first catalyst, then the ring is closed to form isoquinoline under the action of a second catalyst, and finally the tetrahydroisoquinoline structure is obtained by reduction through a reducing agent.
< advantageous effects of the present invention >
The synthesis method has the advantages of low price and easy obtainment of used raw materials, mild reaction conditions, no use of high-risk reaction, simple requirement on used equipment, high yield, lower total cost, suitability for large-scale industrial production and good application prospect.
Drawings
FIG. 1 is a spectrum of Compound 6 of example 8.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
The synthesis method of the sitaxel intermediate 5,7-dichloro-1,2,3,4-tetrahydroisoquinoline hydrochloride comprises the following steps:
(1) Iodination reaction: after hydrogen is extracted from the compound 1 by n-butyl lithium, the compound reacts with iodine to obtain a compound 2;
(2) Amidation reaction: condensing the compound 2 with a condensing agent to obtain an intermediate state; then condensing with methyl methoxy amine hydrochloride in the presence of organic alkali to obtain a compound 3;
(3) Reduction reaction: reducing the compound 3 with a reducing agent to obtain a compound 4;
(4) Coupling reaction: in the first stage, a compound 4 is catalyzed by a first catalyst in the presence of alkali and is coupled with trimethylsilyl acetylene; in the second stage, the second catalyst is used for catalyzing, and the second catalyst reacts with ammonia water to close a ring to obtain a compound 5;
(5) Reduction reaction: the compound 5 is reduced by a reducing agent in the presence of Lewis acid, and is acidified by an acidifying agent to obtain a compound 6.
The condensing agent used in the step (2) is CDI or EDCI; the organic base is diisopropylethylamine or triethylamine;
and/or the reducing agent used in the step (3) is diisobutylaluminum hydride;
and/or, in the step (4), in the first stage, the used base is triethylamine or diisopropylethylamine, and the first catalyst is a mixed reagent comprising a palladium reagent, a copper reagent and a phosphine reagent; in the second stage, the second catalyst is a copper reagent;
and/or, in the step (5), the reducing agent is sodium borohydride or potassium borohydride, and the Lewis acid is nickel chloride hexahydrate; the acidifying agent is hydrochloric acid.
In the present invention, in step (1), the molar ratio of compound 1, n-butyllithium and iodine is 1.0 to 3.0.
And/or, in step (1), the volume ratio of compound 1 to the reaction solvent is 1.0.
In the invention, in the step (2), the molar ratio of the compound 2, the condensing agent, the methylmethoxyamine hydrochloride and the organic base is 1.0-1.3;
and/or, in the step (2), the volume ratio of the compound 2 to the reaction solvent is 1.0.
In the present invention, in step (3), the molar ratio of compound 3 to the reducing agent is 1.0 to 1.5.
And/or, in the step (3), the volume ratio of the compound 2 to the reaction solvent is 1.0.
In the present invention, in the step (4), in the first stage, the molar ratio of the compound 4, the base, the palladium reagent, the copper reagent, the phosphine reagent, and the trimethylsilylacetylene is 1.0 to 2.0 to 2.5: 0.04-0.1; in the second stage, the molar ratio of the compound 4, the second catalyst and the ammonia water is 1.0-0.05;
and/or, in step (4), in the first stage, the volume ratio of compound 2 to reaction solvent is 1.0; in the second stage, the volume ratio of compound 2 to the reaction solvent was 1.0.
In the present invention, in step (5), the molar ratio of compound 5, reducing agent, and lewis acid is 1.0 to 2.5 to 3.0.
And/or, in the step (5), the volume ratio of the compound 2 to the reaction solvent is 1.
In the invention, the reaction solvent used in the step (1) is tetrahydrofuran;
and/or the reaction solvent used in the step (2) is tetrahydrofuran or dichloromethane;
and/or the reaction solvent used in the step (3) is dichloromethane, toluene or tetrahydrofuran;
and/or, in the step (4), the reaction solvent used in the first stage is dichloromethane or dichloroethane; the reaction solvent used in the second stage is ethanol;
and/or the reaction solvent used in step (5) is methanol.
In the invention, in the step (1), the reaction temperature of the reaction solvent is-80 to-70 ℃ when the n-butyl lithium is dripped, and the reaction temperature of the reaction solvent is-80 to-70 ℃ when the iodine is dripped;
and/or, in the step (2), the reaction temperature of adding the condensing agent is 20-25 ℃, and the reaction temperature of dropwise adding the organic base is 20-25 ℃;
and/or, in the step (3), the reaction temperature of dropwise adding the reducing agent is-80 to-70 ℃;
and/or, in the step (4), the reaction temperature is 30-40 ℃ in the first stage, and the reaction temperature is 65-70 ℃ in the second stage;
and/or, in the step (5), the reaction temperature of adding the reducing agent is 0-10 ℃.
< example >
The reaction route of the synthetic method adopted by the invention is as follows:
EXAMPLE 1 preparation of Compound 2
To Compound 1 (100.0g, 0.524mol, 1.0eq) was added tetrahydrofuran (800 mL). Under the protection of nitrogen, the temperature is reduced to minus 80 to minus 70 ℃, 2.5M butyl lithium (0.524mL, 1.31mol and 2.5eq) is dripped, and the temperature is controlled to minus 80 to minus 70 ℃. After the dripping is finished, the reaction is kept for 1h. Iodine (146.2g, 0.576mol, 1.1eq) is dissolved in tetrahydrofuran (500 mL) and dropped at the temperature of-80 to-70 ℃. After dropping, the temperature is kept for 1h, and then the temperature is slowly raised to-30 ℃. The reaction was slowly quenched into 20% citric acid (800 mL) and extracted with ethyl acetate (600mL × 2). The organic phases were combined and washed with 5% sodium bisulfite (500 mL) and saturated brine (500 mL). The organic phase was concentrated to give Compound 2 (122.9g, 0.388mol) in 74% yield.
EXAMPLE 2 preparation of Compound 3
To a solution of Compound 2 (110g, 0.347mol, 1.0eq) in tetrahydrofuran (880 mL) was added CDI (61.9g, 0.382mol, 1.1eq) in portions under nitrogen protection, and stirred at 20-25 ℃ for 2h. N-methyl methoxy amine hydrochloride (37.1g, 0.382mol, 1.1eq) is added, diisopropyl ethylamine (58.2g, 0.451mol, 1.3eq) is added dropwise, the temperature is controlled at 20-25 ℃, and stirring is carried out for 12h after dropwise addition. Water (880 mL) was added, the pH was adjusted to 4-5 with concentrated hydrochloric acid, and extraction was performed with ethyl acetate (550 mLx 2). The organic phases were combined and washed with saturated brine (550 mL). The organic phase was concentrated to give Compound 3 (113.4g, 0.316mol) in 91% yield.
EXAMPLE 3 preparation of Compound 3 II
To a solution of Compound 2 (110g, 0.347mol, 1.0eq) in dichloromethane (880 mL) was added EDCI (86.5g, 0.451mol, 1.3eq) in portions under nitrogen protection, N-methylmethoxyamine hydrochloride (44.0g, 0.451mol, 1.3eq) in portions at 20 to 25 ℃ and triethylamine (87.6g, 0.868mol, 2.5eq) was added dropwise at 20 to 25 ℃ and stirred for 12 hours after completion of dropwise addition. Water (880 mL) was added, the pH was adjusted to 4-5 with concentrated hydrochloric acid, the layers were separated, and the aqueous layer was extracted with dichloromethane (550 mLx 2). The organic phases were combined and washed with saturated brine (550 mL). The organic phase was concentrated to give Compound 3 (107.3g, 0.298mol) in 86% yield.
EXAMPLE 4 preparation of Compound 4
Dissolving the compound 3 (100g, 0.278mol, 1.0eq) in dichloromethane (800 mL), and cooling to-80-70 ℃ under the protection of nitrogen. 1.0M DIBAL-H (361mL, 0.361mol, 1.3eq) is added dropwise, the temperature is controlled between minus 80 ℃ and minus 70 ℃, and the temperature is kept for 2 hours after the dropwise addition. The reaction was slowly quenched into saturated ammonium chloride (800 mL) and the temperature controlled at less than 5 ℃. Filtering with diatomite, and separating. The aqueous phase was extracted with dichloromethane (500mL. Times.2), and the organic phases were combined and washed with 10% citric acid (800 mL) and saturated brine (500 mL), respectively. The organic phase was concentrated to give compound 4 (69.5g, 0.231mol) in 83% yield.
EXAMPLE 5 preparation of Compound 4
Dissolving compound 3 (100g, 0.278mol, 1.0eq) in toluene (800 mL), and cooling to-80-70 ℃ under the protection of nitrogen. 1.0M DIBAL-H (361mL, 0.361mol, 1.3eq) is added dropwise, the temperature is controlled between 80 ℃ below zero and 70 ℃ below zero, and the temperature is kept for 2 hours after the dropwise addition. The reaction was slowly quenched into saturated ammonium chloride (800 mL) and the temperature controlled at less than 5 ℃. Filtering with diatomite, and separating. The aqueous phase was extracted with toluene (500mL. Times.2), and the organic phases were combined and washed with 10% citric acid (800 mL) and saturated brine (500 mL), respectively. The organic phase was concentrated to give compound 4 (62.7g, 0.209mol) in 75% yield.
EXAMPLE 6 preparation of Compound 5
Compound 4 (60g, 0.199mol, 1.0eq), triethylamine (40.2g, 0.398mol, 2.0eq), cuprous iodide (3.8g, 0.02mol, 0.1eq), triphenylphosphine (2.1g, 0.008mol, 0.04eq) and dichloromethane (600 mL) were charged into a reaction flask, respectively. After nitrogen replacement, bis (triphenylphosphine) palladium dichloride (2.8g, 0.004mol, 0.02eq) is added, trimethylsilylacetylene (27.5g, 0.28mol, 1.4eq) is added dropwise, and the temperature is controlled at 30-40 ℃. After dropping, the reaction is kept for 12h. The temperature was reduced to 20-25 deg.C, water (240 mL) was added, the pH was adjusted to 6-7 with 1N HCl, and the layers were separated. The organic phase was concentrated to dryness. Ethanol (420 mL), cuprous iodide (1.9g, 0.01mol, 0.05eq), 28% ammonia (50.0g, 0.4mol, 2.0eq) were added. Heating to 65-70 ℃ and reacting for 8 hours. The reaction mixture was concentrated, ethyl acetate (120 mL) and N-heptane (480 mL) were added, and the mixture was washed with 1N HCl (200 mL) and saturated brine (300 mL), respectively, and the layers were separated. The organic phase was filtered through a pad of silica gel and the filtrate was concentrated to give Compound 5 (28.1g, 0.142mol) in 71% yield.
EXAMPLE 7 preparation of Compound 5
Compound 4 (60g, 0.199mol, 1.0eq), diisopropylethylamine (51.3g, 0.398mol, 2.0eq), cuprous iodide (3.8g, 0.02mol, 0.1eq), triphenylphosphine (2.1g, 0.008mol, 0.04eq) and dichloroethane (600 mL) were charged into a reaction flask, respectively. After nitrogen replacement, bis (triphenylphosphine) palladium dichloride (2.8g, 0.004mol and 0.02eq) is added, trimethylsilylacetylene (27.5g, 0.28mol and 1.4eq) is added dropwise, and the temperature is controlled at 30-40 ℃. After dropping, the reaction is kept for 12h. The temperature was reduced to 20-25 deg.C, water (240 mL) was added, the pH was adjusted to 6-7 with 1N HCl, and the layers were separated. The organic phase was concentrated to dryness. Ethanol (420 mL), cuprous iodide (1.9g, 0.01mol, 0.05eq), 28% ammonia (50.0g, 0.4mol, 2.0eq) were added. Heating to 65-70 ℃ and reacting for 8 hours. The reaction mixture was concentrated, ethyl acetate (120 mL) and N-heptane (480 mL) were added, and the mixture was washed with 1N HCl (200 mL) and saturated brine (300 mL), respectively, and the mixture was separated. The organic phase was filtered through a pad of silica gel and the filtrate was concentrated to give compound 5 (27.2g, 0.137mol) in 69% yield.
EXAMPLE 8 preparation of Compound 6
The reaction flask was charged with Compound 5 (20g, 0.10mol, 1.0eq), nickel chloride hexahydrate (23.7g, 0.10mol, 1.0eq), and methanol (200 mL). Under the protection of nitrogen, sodium borohydride (9.5g, 0.25mol, 2.5eq) is added in batches, the temperature is controlled to be 0-10 ℃, after the addition is finished, the temperature is raised to 20-30 ℃, and the reaction is kept for 8 hours. The reaction was quenched slowly into water (200 mL). The mixture was concentrated under reduced pressure, and the residue was extracted with 10% sodium hydroxide (250 mL) and methylene chloride (100mL. Times.3). The organic phases were combined, filtered through celite, the filtrate was concentrated to the remaining 100mL, concentrated HCl (20 mL) was added dropwise, the temperature was controlled at 0-10 deg.C and stirred for 2h. Filtration and drying gave compound 6 (20.3g, 0.085mol) in 85% yield. HNMR (400MHz, DMSO-d 6): 9.81 (s, 2H), 7.62 (s, 1H), 7.43 (s, 1H), 4.27 (s, 2H), 3.41 (s, 2H), 2.95 (s, 2H).
EXAMPLE 9 preparation of Compound 6
A reaction flask was charged with Compound 5 (20g, 0.10mol, 1.0eq), nickel chloride hexahydrate (23.7g, 0.10mol, 1.0eq), and methanol (200 mL). Under the protection of nitrogen, adding potassium borohydride (13.5g, 0.25mol, 2.5eq) in batches, controlling the temperature at 0-10 ℃, heating to 20-30 ℃ after the addition, and keeping the temperature for reaction for 8 hours. The reaction was quenched slowly into water (200 mL). The mixture was concentrated under reduced pressure, and the residue was extracted with 10% sodium hydroxide (250 mL) and methylene chloride (100mL. Times.3). The organic phases were combined, filtered through celite, the filtrate was concentrated to the remaining 100mL, concentrated HCl (20 mL) was added dropwise, the temperature was controlled at 0-10 deg.C and stirred for 2h. After filtration and drying, compound 6 (18.8g, 0.079mol) was obtained in 79% yield. HNMR (400MHz, DMSO-d 6): 9.81 (s, 2H), 7.62 (s, 1H), 7.43 (s, 1H), 4.27 (s, 2H), 3.41 (s, 2H), 2.95 (s, 2H).
The spectrum of compound 6 is shown in FIG. 1.
In conclusion, the synthesis method of the sitaxel intermediate 5,7-dichloro-1,2,3,4-tetrahydroisoquinoline hydrochloride disclosed by the invention has the advantages of low price and easiness in obtaining of used raw materials, mild reaction conditions, no use of high-risk reaction, simple requirement on used equipment, high yield, lower total cost, suitability for large-scale industrial production and good application prospect.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (17)
1. The synthesis method of the sitaxel intermediate 5,7-dichloro-1,2,3,4-tetrahydroisoquinoline hydrochloride is characterized by comprising the following steps:
(1) Iodination reaction: after hydrogen is extracted from the compound 1 by n-butyl lithium, the compound reacts with iodine to obtain a compound 2;
(2) Amidation reaction: condensing the compound 2 with a condensing agent to obtain an intermediate state; then condensing with methyl methoxy amine hydrochloride in the presence of organic alkali to obtain a compound 3;
(3) Reduction reaction: reducing the compound 3 to obtain a compound 4;
(4) Coupling reaction: in the first stage, a compound 4 is catalyzed by a first catalyst and coupled with trimethylsilyl acetylene in the presence of alkali; in the second stage, the second catalyst is used for catalyzing, and the second catalyst reacts with ammonia water to close the ring to obtain a compound 5;
(5) Reduction reaction: reducing the compound 5 by a reducing agent in the presence of Lewis acid, and acidifying by an acidifying agent to obtain a compound 6;
the condensing agent used in the step (2) is CDI or EDCI; the organic base is diisopropylethylamine or triethylamine;
the reducing agent used in the step (3) is diisobutylaluminum hydride;
in the step (4), in the first stage, the used base is triethylamine or diisopropylethylamine, and the first catalyst is a mixed reagent of bis (triphenylphosphine) palladium dichloride, cuprous iodide and triphenylphosphine; in the second stage, the second catalyst is cuprous iodide;
in the step (5), the reducing agent is sodium borohydride or potassium borohydride, and the Lewis acid is nickel chloride hexahydrate; the acidifying agent is hydrochloric acid.
2. The synthesis method of sitagliptin intermediate 5,7-dichloro-1,2,3,4-tetrahydroisoquinoline hydrochloride according to claim 1, characterized in that,
in the step (1), the molar ratio of the compound 1, n-butyllithium and iodine is 1.0 to 3.0.
3. The synthesis method of sitagliptin intermediate 5,7-dichloro-1,2,3,4-tetrahydroisoquinoline hydrochloride according to claim 1, characterized in that,
in the step (1), the volume ratio of the compound 1 to the reaction solvent is 1.0.
4. The synthesis method of sitagliptin intermediate 5,7-dichloro-1,2,3,4-tetrahydroisoquinoline hydrochloride according to claim 1, characterized in that,
in the step (2), the molar ratio of the compound 2, the condensing agent, the methylmethoxyamine hydrochloride and the organic base is 1.0-1.3.
5. The synthesis method of sitagliptin intermediate 5,7-dichloro-1,2,3,4-tetrahydroisoquinoline hydrochloride according to claim 1, characterized in that,
in the step (2), the volume ratio of the compound 2 to the reaction solvent is 1.0.
6. The synthesis method of sitagliptin intermediate 5,7-dichloro-1,2,3,4-tetrahydroisoquinoline hydrochloride according to claim 1, characterized in that,
in the step (3), the molar ratio of the compound 3 to the reducing agent is 1.0 to 1.5.
7. The synthesis method of the sitaxel intermediate 5,7-dichloro-1,2,3,4-tetrahydroisoquinoline hydrochloride according to claim 1, wherein,
in the step (3), the volume ratio of the compound 3 to the reaction solvent is 1.0.
8. The synthesis method of sitagliptin intermediate 5,7-dichloro-1,2,3,4-tetrahydroisoquinoline hydrochloride according to claim 1, characterized in that,
in the step (4), in the first stage, the molar ratio of the compound 4, the alkali, the palladium reagent, the copper reagent, the phosphine reagent and the trimethylsilyl acetylene is 1.0-2.5; in the second stage, the molar ratio of the compound 4, the copper reagent and the ammonia water is 1.0 to 0.05.
9. The synthesis method of sitagliptin intermediate 5,7-dichloro-1,2,3,4-tetrahydroisoquinoline hydrochloride according to claim 1, characterized in that,
in the step (4), in the first stage, the volume ratio of the compound 4 to the reaction solvent is 1.0; in the second stage, the volume ratio of compound 4 to the reaction solvent was 1.0.
10. The synthesis method of sitagliptin intermediate 5,7-dichloro-1,2,3,4-tetrahydroisoquinoline hydrochloride according to claim 1, characterized in that,
in the step (5), the molar ratio of the compound 5, the reducing agent and the lewis acid is 1.0 to 2.5 to 3.0.
11. The synthesis method of sitagliptin intermediate 5,7-dichloro-1,2,3,4-tetrahydroisoquinoline hydrochloride according to claim 1, characterized in that,
in the step (5), the volume ratio of the compound 5 to the reaction solvent is 1.
12. The synthesis method of sitagliptin intermediate 5,7-dichloro-1,2,3,4-tetrahydroisoquinoline hydrochloride according to claim 1, characterized in that,
the reaction solvent used in the step (1) is tetrahydrofuran;
the reaction solvent used in the step (2) is tetrahydrofuran or dichloromethane;
the reaction solvent used in the step (3) is dichloromethane, toluene or tetrahydrofuran;
in the step (4), the reaction solvent used in the first stage is dichloromethane or dichloroethane; the reaction solvent used in the second stage is ethanol;
the reaction solvent used in step (5) is methanol.
13. The synthesis method of sitagliptin intermediate 5,7-dichloro-1,2,3,4-tetrahydroisoquinoline hydrochloride according to claim 1, characterized in that,
in the step (1), the reaction temperature when n-butyllithium is dropped is-80 to-70 ℃, and the reaction temperature of the reaction solvent when iodine is dropped is-80 to-70 ℃.
14. The synthesis method of sitagliptin intermediate 5,7-dichloro-1,2,3,4-tetrahydroisoquinoline hydrochloride according to claim 1, characterized in that,
in the step (2), the reaction temperature of adding the condensing agent is 20-25 ℃, and the reaction temperature of dropwise adding the organic base is 20-25 ℃.
15. The synthesis method of sitagliptin intermediate 5,7-dichloro-1,2,3,4-tetrahydroisoquinoline hydrochloride according to claim 1, characterized in that,
in the step (3), the reaction temperature of dropwise adding the reducing agent is-80 to-70 ℃.
16. The synthesis method of sitagliptin intermediate 5,7-dichloro-1,2,3,4-tetrahydroisoquinoline hydrochloride according to claim 1, characterized in that,
in the step (4), the reaction temperature is 30-40 ℃ in the first stage, and 65-70 ℃ in the second stage.
17. The synthesis method of the sitaxel intermediate 5,7-dichloro-1,2,3,4-tetrahydroisoquinoline hydrochloride according to claim 1, wherein,
in the step (5), the reaction temperature of adding the reducing agent is 0-10 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210254550.0A CN114524767B (en) | 2022-03-11 | 2022-03-11 | Synthesis method of sitaxel intermediate 5,7-dichloro-1,2,3,4-tetrahydroisoquinoline hydrochloride |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210254550.0A CN114524767B (en) | 2022-03-11 | 2022-03-11 | Synthesis method of sitaxel intermediate 5,7-dichloro-1,2,3,4-tetrahydroisoquinoline hydrochloride |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114524767A CN114524767A (en) | 2022-05-24 |
| CN114524767B true CN114524767B (en) | 2022-10-18 |
Family
ID=81626548
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210254550.0A Active CN114524767B (en) | 2022-03-11 | 2022-03-11 | Synthesis method of sitaxel intermediate 5,7-dichloro-1,2,3,4-tetrahydroisoquinoline hydrochloride |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114524767B (en) |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110922393A (en) * | 2012-07-25 | 2020-03-27 | 诺华股份有限公司 | LFA-1 inhibitors and polymorphs thereof |
| CN112321506B (en) * | 2020-11-26 | 2021-12-24 | 江西天戌药业有限公司 | Preparation method of 5, 7-dichloro-1, 2,3, 4-tetrahydroisoquinoline |
| CN112500343B (en) * | 2020-12-26 | 2023-04-07 | 山东金城柯瑞化学有限公司 | Synthesis method of 5, 7-dichloro-1, 2,3, 4-tetrahydroisoquinoline hydrochloride |
-
2022
- 2022-03-11 CN CN202210254550.0A patent/CN114524767B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN114524767A (en) | 2022-05-24 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108203404A (en) | (R) synthetic method of -3- Phenylpiperidines or/and the chiral intermediate of (S) -3- Phenylpiperidines and Ni Lapani | |
| EP3080086B1 (en) | Process of making adamantanamides | |
| CN102229613B (en) | New process for synthesis of asenapine | |
| JPH0791244B2 (en) | Fluoxetine manufacturing method | |
| CN115181066B (en) | Synthesis method of 6-chloro-2-methyl-2H-indazole-5-amine | |
| US20040106818A1 (en) | Process for the preparation of cyclohexanol derivatives | |
| CN113248432B (en) | Novel method for preparing Luo Shasi other intermediates in high yield | |
| CN103420855A (en) | Trans-4-amino cyclohexylmethanol hydrochloride and preparation method thereof | |
| CN114524767B (en) | Synthesis method of sitaxel intermediate 5,7-dichloro-1,2,3,4-tetrahydroisoquinoline hydrochloride | |
| CN109796351B (en) | Novel preparation method of drotaverine hydrochloride intermediate | |
| CN106831441A (en) | A kind of preparation method of cinacalcet hydrochloride | |
| CN102321045B (en) | Method for preparing high morphine hydrochloride | |
| CN111100042B (en) | Preparation method of 2-methoxy-5-sulfonamide benzoic acid | |
| CN114805167A (en) | Preparation method of brivaracetam | |
| KR20100118747A (en) | Improved preparation method of sarpogrelate hydrochloride | |
| CN109678738B (en) | Method for synthesizing (2S,3S) -3-amino-bicyclo [2.2.2] octane-2-formate | |
| CN111620802A (en) | Preparation method of cefditoren intermediate (R) -1-benzyl-3-aminopyrrolidine | |
| CN112479993A (en) | Synthetic method applied to KRAS inhibitor drug heterocyclic intermediate | |
| CN101412678B (en) | Method for synthesizing memantine hydrochloride | |
| CN111825688B (en) | Preparation method of 6-tert-butyl-3 ', 3', 3-trimethylpyrano [3,2-a ] carbazole | |
| CN110724098A (en) | Synthetic method of 5, 7-dichloro-1, 2,3, 4-tetrahydroisoquinoline-6-carboxylic acid hydrochloride | |
| WO2015012271A1 (en) | Method for producing heterocyclic compound | |
| JP2000109462A (en) | Production of 8-benzylaminoquioline | |
| KR101479986B1 (en) | New process for the synthesis of ivabradine and addition salts thereof with a pharmaceutically acceptable acid | |
| EP1730102B1 (en) | A novel catalytic process for the production of 3,3 , 4,4'-tetraminobiphenyl |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |