CN114149384A - Synthetic method of quetiapine - Google Patents

Synthetic method of quetiapine Download PDF

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CN114149384A
CN114149384A CN202110811560.5A CN202110811560A CN114149384A CN 114149384 A CN114149384 A CN 114149384A CN 202110811560 A CN202110811560 A CN 202110811560A CN 114149384 A CN114149384 A CN 114149384A
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compound
tert
organic solvent
prepared
ethanol
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朱其明
王海旭
崔雨
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Nanning Normal University
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Nanning Normal University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D281/02—Seven-membered rings
    • C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D281/12—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with two six-membered rings
    • C07D281/16—[b, f]-condensed
    • 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 discloses a method for preparing quetiapine, which takes 11-chlorodibenzo [ b, f ] [1,4] thiazoline, 1, 4-diazabicyclo [2.2.2] octane and 2- (tert-butyldimethylsilyl) oxy) ethanol as reaction raw materials to obtain an intermediate, and finally hydrolyzes under an acidic condition to obtain the quetiapine; the generated impurities are relatively reduced, the environmental pollution is less, the method just meets the currently advocated green synthesis, and the friendly development of synthesis production and environment is reflected.

Description

Synthetic method of quetiapine
Technical Field
The invention belongs to the field of medicines, and particularly relates to a preparation method of atypical antipsychotic quetiapine.
Background
Quetiapine (Quetiapine) is an atypical antipsychotic drug developed by AstraZeneca (AstraZeneca) in the united kingdom and approved by the U.S. FDA for marketing in 1997. Has effects in blocking various neurotransmitter receptors, such as serotonin receptor (5-HT), dopamine receptor (D), adrenergic receptor (alpha), cholinergic receptor (M), etc., and has antipsychotic, antidepressant, anxiolytic, and tranquilizing effects. In 1997, quetiapine was first approved for the treatment of schizophrenia; approved for the treatment of acute manic episodes in 2004; approved for treatment of bipolar disorder in 2006; in 2007, the appearance of sustained release formulations allowed better patient compliance; in 2009, major depression was increased in the indication. Schizophrenia is a serious mental disorder characterized by distorted thinking, opinion, mood, language, self-consciousness and behavior, with common symptoms including auditory hallucinations and delusions. More than 2100 million patients with schizophrenia have been reported worldwide by the world health organization 2016, and schizophrenia is associated with a large number of disabilities and may affect educational efficacy and occupational performance. The early mortality rate of schizophrenic patients is 2-2.5 times higher than that of common people, and the schizophrenic patients are often subjected to discrimination and infringement. Depression is a mental disorder that appears to be far from us but is truly present. About 4 hundred million people worldwide suffer from depression, with a swedish incidence of 6.16%, 4.45% in the united states, and 3.0% in china. Psychomental diseases account for more than 20% of life loss years caused by disabilities. Therefore, the quetiapine has a wide market prospect as an atypical antipsychotic.
The synthesis and development of the drug have great market value, and the current mature synthesis process comprises the following steps: and (5) route one.
Figure 1
Route one: taking diethanolamine (3) as a raw material, and chlorinating the diethanolamine in dichloroethane through thionyl chloride to obtain di (2-chloroethyl) amine hydrochloride (4); under the alkaline condition, (4) reacting with acetyl chloride through acetylation reaction (5); heating and refluxing the recrystallized (5), diglycolamine and water to react to obtain (6); and then 3 is obtained through deacetylation reaction. Dibenzo [ b, f ]][1,4]Sulphur nitrogen
Figure BDA0003168420450000022
Under the action of N, N-dimethylaniline, 11(10H) -ketone 1 is chloridized by phosphorus oxychloride to obtain an intermediate 2, which directly reacts with 3 under the action of potassium carbonate to generate nucleophilic substitution reactionShould obtain 4.
And a second route:
Figure BDA0003168420450000031
and a second route: 1 under the action of phosphorus oxychloride and N, N-dimethylaniline, the chloro-product 11-chlorodibenzo [ b, f ] is prepared][1,4]Sulphur nitrogen
Figure BDA0003168420450000032
2, directly carrying out nucleophilic substitution reaction on the crude product 2 and piperazine without purification to obtain 11-piperazinyldibenzo [ b, f][1,4]Sulphur nitrogen
Figure BDA0003168420450000033
4, directly carrying out nucleophilic substitution reaction on the crude product 4 and 2- (2-chloroethoxy) ethanol (5) in N-methylpyrrolidone (NMP) under the condition that sodium carbonate is used as alkali and sodium iodide is used as a catalyst without purification to obtain 5.
The two routes are as follows: the currently adopted synthesis method is multi-step synthesis, the steps are relatively complicated, the route is relatively long, the operation process is relatively complex, the resource waste phenomenon is relatively serious, the pollution is relatively large, the total yield is relatively low, and the production cost is relatively high. We improve the technology according to the above disadvantages and develop a high-efficiency and high-atom-economy quetiapine synthesis technology.
Disclosure of Invention
In order to solve the problems in the prior art, the invention provides a new reaction system for synthesizing quetiapine, and the method is simple and efficient to operate. The technical scheme of the invention achieves the following beneficial technical effects:
1. no catalyst is used in the reaction, and the problems of heavy metal exceeding and the like do not need to be considered in the post-treatment process;
2. the generated impurities are relatively reduced, the environmental pollution is less, the method just meets the currently advocated green synthesis, and the friendly development of synthesis production and environment is reflected.
In order to solve the technical problem, the invention provides the following technical scheme:
a process for preparing quetiapine characterized in that the process comprises the steps of:
step (1): taking the compounds 1,2 and 3 as raw materials to prepare a compound 4;
Figure BDA0003168420450000041
wherein X represents a leaving group, preferably halogen, more preferably Cl, Br, I; r represents H or a protecting group;
wherein, when R represents a protecting group, the method further comprises the step (2) of deprotection reaction:
step (2):
Figure BDA0003168420450000042
in the technical scheme of the invention, the protecting group is preferably 2- (tert-butyldimethylsilyl) oxy).
In the technical scheme of the invention, the compound 1 in the step (1) is prepared by the following method:
with dibenzo [ b, f ]][1,4]Thiazolin-11 (10H) -ones and POCl3Preparing 11-chlorodibenzo [ b, f ] as reaction raw materials][1,4]Thiazoline (compound 1),
Figure BDA0003168420450000051
in the technical scheme of the invention, the compound 3 in the step (1) is prepared by the following method:
the 2- (tert-butyldimethylsilyl) oxy) ethanol (compound 3) is prepared by taking ethylene glycol and tert-butylchlorodimethylsilane as reaction raw materials
Figure BDA0003168420450000052
In the technical scheme of the invention, the preparation of the compound 1 comprises the following steps:
with dibenzo [ b, f ]][1,4]Thiazolin-11 (10H) -ones and POCl3The compound 1 is prepared by taking N, N-dimethylaniline as a catalyst in an organic solvent as a reaction raw material.
In the above technical solution, the organic solvent is selected from one of toluene, DMSO, DMF, dioxane, tetrahydrofuran, acetonitrile, chloroform, dichloromethane, ethyl acetate, ethanol, acetonitrile, methanol, propanol, and isopropanol, or any combination thereof.
In the technical scheme, the reaction temperature is 80-140 ℃.
In the technical scheme of the invention, the preparation of the compound 3 comprises the following steps:
the compound 3 is prepared by taking ethylene glycol and tert-butylchlorodimethylsilane as reaction raw materials in an organic solvent in the presence of alkali.
In the above technical solution, the organic solvent is selected from one of toluene, DMSO, DMF, dioxane, tetrahydrofuran, acetonitrile, chloroform, dichloromethane, ethyl acetate, ethanol, acetonitrile, methanol, propanol, and isopropanol, or any combination thereof.
In the above technical scheme, the alkali is selected from inorganic alkali or organic alkali, and the inorganic alkali is selected from Na2CO3、NaHCO3、CS2CO3、NaOH、K2CO3、KOH、K3PO4One or any combination of t-BuOK; the organic base is selected from one or any combination of triethylamine, DMAP (4-dimethylaminopyridine), imidazole, DIPEA (N, N-diisopropylethylamine) and pyridine.
In the technical scheme, the molar ratio of the ethylene glycol to the tert-butylchlorodimethylsilane is 1: 1-2.
In the above technical scheme, the reaction temperature is 0 ℃ to room temperature.
In the technical scheme of the invention, the preparation of the step (1) comprises the following steps:
the compound 4 is prepared by using 11-chlorodibenzo [ b, f ] [1,4] thiazoline (compound 1), 1, 4-diazabicyclo [2.2.2] octane (compound 2), 2- (tert-butyldimethylsilyl) oxy) ethanol (compound 3) as a raw material in an organic solvent in the presence of a base.
In the above technical solution, the organic solvent is selected from one of toluene, DMSO, DMF, dioxane, tetrahydrofuran, acetonitrile, chloroform, dichloromethane, ethyl acetate, ethanol, acetonitrile, methanol, propanol, and isopropanol, or any combination thereof.
In the above technical solution, the organic solvent is preferably DMSO.
In the above technical scheme, the alkali is selected from inorganic alkali or organic alkali, and the inorganic alkali is selected from Na2CO3、NaHCO3、CS2CO3、NaOH、K2CO3、KOH、K3PO4One or any combination of t-BuOK; the organic base is selected from one or any combination of triethylamine, DMAP (4-dimethylaminopyridine), imidazole, DIPEA (N, N-diisopropylethylamine) and pyridine.
In the above technical scheme, the alkali is preferably Na2CO3。
In the above technical scheme, the reaction temperature is 40-120 ℃, preferably 60-100 ℃, and most preferably 60 ℃.
In the above technical scheme, the reaction time is 4-24 hours, preferably 8-12 hours, and most preferably 12 hours.
In the technical scheme, the dosage ratio of the compound 1, the compound 2 and the compound 3 is 1-2: 1-2:1-2, and preferably 1:2: 1.
In the above technical scheme, the ratio of the amount of the base to the amount of the compound 1 is 1-2:1-2, preferably 2: 1.
in the technical scheme of the invention, the preparation of the step (2) comprises the following steps:
the compound 4 is used as a raw material, and in an organic solvent, under the acidic condition, deprotection is carried out to prepare quetiapine.
In the above technical solution, the organic solvent is selected from one of toluene, DMSO, DMF, dioxane, tetrahydrofuran, acetonitrile, chloroform, dichloromethane, ethyl acetate, ethanol, acetonitrile, methanol, propanol, and isopropanol, or any combination thereof.
In the above technical solution, the organic solvent is preferably dichloromethane.
In the above technical solution, the deprotection is performed under acidic condition, and the acid is hydrochloric acid, preferably a mixed solution of hydrochloric acid and dioxane.
In the technical scheme, the deprotection reaction temperature is 0-room temperature.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
The technical scheme of the invention is further detailed and completely explained by combining the embodiment.
Example 12- (tert-Butyldimethylsilyl) oxy) ethanol
Figure BDA0003168420450000071
To ethane-1, 2-diol (27.5g,440mmol), anhydrous CH at room temperature2Cl2(550mL) to a solution was added triethylamine (53.53g,74mL,530mmol), the mixture was cooled to 0 deg.C and dissolved in CH dropwise over 1 hour2Cl2Tert-butylchlorodimethylsilane (66.5g,440mol) (150 mL). The mixture was stirred at room temperature overnight. The reaction mixture was washed with saturated NH4Aqueous Cl (100mL) was quenched and separated. The aqueous phase was extracted with methyl tert-butyl ether (2X 100 mL). The combined organic layers were concentrated in vacuo and the residue was redissolved in methyl tert-butyl ether (100 mL). The methyl tert-butyl ether layer was washed with water (2 × 125mL) and brine (125mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 2- (tert-butyldimethylsilyl) oxy) ethanol (69.5g, 90%).
Example Synthesis of 211-chlorodibenzo [ b, f ] [1,4] thiazoline
Figure BDA0003168420450000072
Dibenzo [ b, f ] s were sequentially added to a dry 100mL Young's reaction tube][1,4]Thiazolin-11 (10H) -one (9.988g,44mmol), POCl3(7.4g,4.5ml,48.4mmol), N, N-dimethylaniline (10.6g,11ml,88mmol) and a stirring magnet, vacuumizing the reaction tube, introducing argon, adding a solvent toluene, sealing, and placing the reaction tube in an oil bath kettle at 110 ℃ for reaction for 12 hours. After the reaction was completed, the reaction system was cooled to room temperature, 150ml of water was added thereto, followed by extraction with ethyl acetate (4X 300 ml), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The crude product obtained was purified with ethyl acetate: separating and purifying by column chromatography using mixed solvent of petroleum ether (1:10,1:5) as eluent to obtain corresponding target product 11-chlorodibenzo [ b, f][1,4]The thiazoline yield was (8.516, 79%).
EXAMPLE 3 Synthesis of Compound 4
With 11-chlorodibenzo [ b, f ]][1,4]Thiazoline (245mg,1mmol), 1, 4-diazabicyclo [2.2.2]]Octane (224mg,2mmol), 2- (tert-butyldimethylsilyl) oxy) ethanol (176mg,1mmol) as starting material, Cs2CO3As a base, DMSO as a solvent was reacted at 80 ℃ for 12 hours, and then the objective product 4(198mg, 40%) was obtained by silica gel column chromatography.
Figure BDA0003168420450000081
EXAMPLE 4 preparation of Compound 4 from Compounds 1,2 and 3 under different reaction conditions
The influence of the reaction conditions on the synthesis of compound 4 was investigated by using the same reaction procedure as in example 3, varying the reagents used in the reaction procedure, including base, solvent, reaction temperature, reaction time, with the results as
Table 1:
Figure BDA0003168420450000082
Figure BDA0003168420450000091
TABLE 1 Experimental results for the preparation of Compound 4 under different reaction conditions
EXAMPLE 5 preparation of quetiapine
Figure BDA0003168420450000092
In a round flask, Compound 4(497mg,1mmol), CH was charged2Cl2(5ml), the mixture was cooled to 0 ℃ in an ice/water bath and HCl (1ml,4N-HCl/dioxane) was added, after which the mixture was stirred at room temperature for 3 h. Extraction and column chromatography gave the desired product 5(360mg, 94%). When the amount of compound 4 was increased to (2.485g,5mmol), the yield of the desired product quetiapine was 78% (1.494 g).
The above-mentioned embodiments are merely exemplary embodiments for fully illustrating the present invention, and the scope of the present invention is not limited to the above-mentioned embodiments, but defined by the contents of the claims. All matters disclosed in the specification including the abstract and all methods and steps disclosed herein may be combined in any combination, except combinations where the features and/or steps are mutually exclusive. Each feature disclosed in this specification, including the abstract, can be replaced by alternative features serving the same, equivalent or similar purpose, unless expressly stated otherwise. Thus, unless expressly stated otherwise, each feature disclosed is one example only of a generic series of equivalent or similar features. Those skilled in the art should also realize that such equivalent substitutions and alterations can be made without departing from the spirit and scope of the present invention. Such modifications are also intended to be within the scope of the present invention. Each reference cited in this application is incorporated herein in its entirety.

Claims (10)

1. A synthetic method of quetiapine is characterized by comprising the following steps:
step (1): taking the compounds 1,2 and 3 as raw materials to prepare a compound 4;
Figure FDA0003168420440000011
wherein X represents a leaving group, preferably halogen, more preferably Cl, Br, I; r represents H or a protecting group;
wherein, when R represents a protecting group, the method further comprises the step (2) of deprotection reaction:
step (2):
Figure FDA0003168420440000012
2. the process according to claim 1, wherein the protecting group is preferably 2- (tert-butyldimethylsilyl) oxy).
3. The method according to claim 1 or 2, wherein the compound 1 in step (1) is prepared by the following method:
with dibenzo [ b, f ]][1,4]Thiazolin-11 (10H) -ones and POCl3Preparing 11-chlorodibenzo [ b, f ] as reaction raw materials][1,4]Thiazoline (compound 1),
Figure FDA0003168420440000013
4. the method of claim 2, wherein the compound 3 in step (1) is prepared by the following method:
the 2- (tert-butyldimethylsilyl) oxy) ethanol (compound 3) is prepared by taking ethylene glycol and tert-butylchlorodimethylsilane as reaction raw materials
Figure FDA0003168420440000021
5. The method of claim 1 or 2, wherein the preparation of compound 1 comprises the steps of:
with dibenzo [ b, f ]][1,4]Thiazolin-11 (10H) -ones and POCl3The compound 1 is prepared by taking N, N-dimethylaniline as a catalyst in an organic solvent as a reaction raw material.
6. The method according to claim 4, wherein the organic solvent is selected from one of toluene, DMSO, DMF, dioxane, tetrahydrofuran, acetonitrile, chloroform, dichloromethane, ethyl acetate, ethanol, acetonitrile, methanol, propanol, isopropanol or any combination thereof.
7. The method of claim 2, wherein the preparation of compound 3 comprises the steps of:
the compound 3 is prepared by taking ethylene glycol and tert-butylchlorodimethylsilane as reaction raw materials in an organic solvent in the presence of alkali.
8. The method according to claim 6, wherein the organic solvent is selected from one of toluene, DMSO, DMF, dioxane, tetrahydrofuran, acetonitrile, chloroform, dichloromethane, ethyl acetate, ethanol, acetonitrile, methanol, propanol, isopropanol or any combination thereof.
9. The method of claim 2, wherein the preparing of step (1) comprises the steps of:
the compound 4 is prepared by using 11-chlorodibenzo [ b, f ] [1,4] thiazoline (compound 1), 1, 4-diazabicyclo [2.2.2] octane (compound 2), 2- (tert-butyldimethylsilyl) oxy) ethanol (compound 3) as a raw material in an organic solvent in the presence of a base.
10. The method of claim 2, wherein the preparing of step (2) comprises the steps of: taking a compound 4 as a raw material, and carrying out deprotection in an organic solvent under the acidic condition to prepare quetiapine; the deprotection is carried out under an acidic condition, the acid is hydrochloric acid, and a mixed solution of hydrochloric acid and dioxane is preferred.
CN202110811560.5A 2021-02-05 2021-07-19 Synthetic method of quetiapine Pending CN114149384A (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050080072A1 (en) * 2003-09-01 2005-04-14 Orchid Chemicals & Pharmaceuticals Ltd. Process for the preparation of a thiazepine derivative
CN101190902A (en) * 2007-04-18 2008-06-04 湖南洞庭药业股份有限公司 Method for preparing pharmaceutical pure quetiapine fumarate
CN105859653A (en) * 2016-04-29 2016-08-17 嘉兴学院 Quetiapine synthesizing method
CN106187873A (en) * 2016-07-25 2016-12-07 宜春学院 A kind of aryl amine alkyl oxygen compounds and preparation method thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050080072A1 (en) * 2003-09-01 2005-04-14 Orchid Chemicals & Pharmaceuticals Ltd. Process for the preparation of a thiazepine derivative
CN101190902A (en) * 2007-04-18 2008-06-04 湖南洞庭药业股份有限公司 Method for preparing pharmaceutical pure quetiapine fumarate
CN105859653A (en) * 2016-04-29 2016-08-17 嘉兴学院 Quetiapine synthesizing method
CN106187873A (en) * 2016-07-25 2016-12-07 宜春学院 A kind of aryl amine alkyl oxygen compounds and preparation method thereof

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