CN112939892B - Preparation method of quetiapine - Google Patents
Preparation method of quetiapine Download PDFInfo
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- CN112939892B CN112939892B CN202110308560.3A CN202110308560A CN112939892B CN 112939892 B CN112939892 B CN 112939892B CN 202110308560 A CN202110308560 A CN 202110308560A CN 112939892 B CN112939892 B CN 112939892B
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- quetiapine
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- sulphur nitrogen
- dibenzo
- ethyl acetate
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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
Abstract
The invention discloses a method for synthesizing quetiapine by using a ruthenium catalyst. With 11-piperazinyl dibenzo [ b, f][1,4]Sulphur nitrogen
With diethylene glycol as starting material under ruthenium catalysisUnder the catalytic action of said agent 11- [4- [2- (2-hydroxyethoxy) ethyl-1-piperazinyl is obtained]]-dibenzo [ b, f ]][1,4]Sulphur nitrogen
Description
(I) technical field
The invention belongs to the technical field of medicines, and particularly relates to an antipsychotic drug quetiapine (11- [4- [2- (2-hydroxyethoxy) ethyl-1-piperazinyl)]]-dibenzo [ b, f ]][1,4]Sulphur nitrogen
) The preparation method of (1).
(II) background of the invention
Quetiapine hemifumarate (quetiapine hemifumarate), common name: en ruikang, qi wei, english common name: quetiapine, chemical name is 11- [4- [2- (2-hydroxyethoxy) ethyl]-1-piperazinyl]Dibenzo [ b, f ]][1,4]Nitrogen sulfur
Hemifumarate, developed by AstraZeneca, UK, was approved by the United states FDA for marketing in 1997, which was first marketed in the United kingdom in the same year. The domestic quetiapine produced in 2000 is approved to be on the market, the quetiapine imported in the same year is also registered in China and is on the market in the next year, the quetiapine is an atypical antipsychotic, can block various neurotransmitter receptors such as dopamine and 5-hydroxytryptamine in brain, has stronger antipsychotic effect, and compared with other antipsychotic medicaments, the quetiapine has the characteristics of higher receptor selectivity, no adverse reaction of an extrapyramidal system, good oral absorption and complete metabolism, and is a first-line medicament for clinically treating schizophrenia.
Quetiapine hemifumarate has the structural formula:
11- [4- [2- (2-hydroxyethoxy) ethyl-1-piperazinyl]]-dibenzo [ b, f ]][1,4]Sulphur nitrogen
Is a precursor for the synthesis of quetiapine hemifumarate, which is usually made of 11-piperazinyldibenzo [ b, f][1,4]Sulphur nitrogen
Reacting with 2- (2-chloroethoxy) ethanol. This method has the following disadvantages: the method of using halogenated hydrocarbon to substitute the structural C-N bond has the advantages of easy reaction, low yield, large amount of undesirable waste and high production cost.
Disclosure of the invention
In order to overcome the defects of low yield, more byproducts and high cost in the prior art, the invention provides quetiapine (11- [4- [2- (2-hydroxyethoxy) ethyl-1-piperazinyl)]]-dibenzo [ b, f ]][1,4]Sulphur nitrogen
) The preparation method of (1). The method has the advantages of mild reaction conditions, high atom utilization rate, high product yield, unique byproduct of water, low cost, environmental friendliness and suitability for industrial production.
In order to achieve the purpose, the invention adopts the following technical scheme:
the invention provides a preparation method of quetiapine, which comprises the following steps:
with 11-piperazinyl dibenzo [ b, f][1,4]Sulphur nitrogen
Reacting with diethylene glycol serving as a raw material in a ruthenium catalyst and an organic solvent at 120-160 ℃ (preferably 140 ℃) for 3-10 h (preferably 5 h), and carrying out post-treatment on the obtained reaction liquid to obtain the quetiapine (11- [4- [2- (2-hydroxyethoxy) ethyl-1-piperazinyl)]]-dibenzo [ b, f ]][1,4]Sulphur nitrogen
) (ii) a The ruthenium catalyst, diethylene glycol and 11-piperazinyl dibenzo [ b, f ]][1,4]Sulphur nitrogen
The amount of the substance(s) of0.02-0.05: 1 to 5:1, preferably 0.03:3:1; the ruthenium catalyst is bis (triphenylphosphine) carbonyl acetonitrile ruthenium dichloride, bis (triphenylphosphine) carbonyl ruthenium dichloride monohydrate or tetrakis (triphenylphosphine) ruthenium dichloride, preferably bis (triphenylphosphine) carbonyl acetonitrile ruthenium dichloride.
The reaction equation is as follows:
preferably, the organic solvent is selected from any one of toluene, xylene, DMSO, and t-amyl alcohol, and is more preferably toluene. Aqueous solvents cannot be used because moisture inhibits the reaction.
Preferably, the organic solvent is mixed with 11-piperazinyldibenzo [ b, f ]][1,4]Sulphur nitrogen
The mass ratio of (A) to (B) is 8-10: 1, further preferably 10:1.
further, the post-treatment is as follows: cooling the reaction liquid to room temperature, distilling off the solvent under reduced pressure, adding ethyl acetate for dissolving, washing, drying with anhydrous magnesium sulfate, filtering, distilling off the ethyl acetate from the filtrate under reduced pressure, purifying by using a rapid preparative liquid chromatograph, eluting by using a mixed solution of ethyl acetate and petroleum ether with a volume ratio of 2-20 as an eluent, collecting the eluent containing a target product, and distilling under reduced pressure to obtain quetiapine.
Compared with the prior art, the invention has the beneficial effects that:
11- [4- [2- (2-hydroxyethoxy) ethyl-1-piperazinyl catalyzed by ruthenium and using diethylene glycol as a starting material]]-dibenzo [ b, f ]][1,4]Sulphur nitrogen
The water is the only byproduct in the preparation process, so that the use of a plurality of toxic halogenating reagents is avoided, the atom utilization rate of the reaction is improved, and the green synthesis of the quetiapine is successfully realized.
(IV) detailed description of the preferred embodiments
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. Numerous technical details are set forth in order to provide a thorough understanding of the present invention, including the use of certain specific terms. However, the technical solution claimed in the present application can be implemented without these technical details and without some changes and modifications to the following embodiments.
The yield in the following examples is calculated without considering the purity as:
Y＝(m yield of the product /M Product of )/N Starting materials
m Yield of the product Mass of product containing impurities, M Product of Is the relative molecular mass of the target product, N Starting materials The amount of material that is the reactant for which the amount of material is smaller.
The flash preparative liquid chromatograph used in the following examples was a Biotage purification apparatus, model Biotage Isolera One.
Example 1:
to a 10mL pressure tube was added 1mL of toluene, 0.089g (0.3 mmol) of 11-piperazinyldibenzo [ b, f ]][1,4]Sulphur nitrogen
0.106g (1.0 mmol) of diethylene glycol, 2.30mg (1 mol%) of bis (triphenylphosphine) carbonylacetonitrile dichlororuthenium and stirring. Heating to 140 ℃, reacting for 5h, cooling to room temperature after the reaction is finished, distilling off the solvent under reduced pressure, adding 2mL of ethyl acetate into the residue, washing with water for 2 times, adding anhydrous magnesium sulfate, drying, filtering, distilling off the ethyl acetate from the filtrate under reduced pressure, purifying by using a rapid preparative liquid chromatograph (volume ratio of ethyl acetate to petroleum ether is 5]]-dibenzo [ b, f ]][1,4]Sulphur nitrogen
Oil 0.107g. Yield: 93.0%, HPLC purity: 96.85 percent. 1 H NMR(500MHz,CDCl 3 )δ7.51(d,J＝7.5Hz,1H),7.39(dd,J＝7.7,1.4Hz,1H),7.37–3.28(m,3H),7.18(td,J＝8.0,1.5Hz,1H),7.08(dd,J＝8.0,1.3Hz,1H),6.89(td,J＝7.6,1.4Hz,1H),3.78–3.74(m,2H),3.73–3.69(m,2H),3.69–3.65(m,3H),3.64–3.58(m,5H),2.71–2.62(m,3H),2.61–2.51(m,2H). 13 C NMR(126MHz,CDCl 3 )δ160.60,148.81,139.89,134.02,132.15,132.13,130.79,129.08,128.93,128.27,127.94,125.26,122.83,72.41,72.33,67.43,61.85(2C),61.62,57.93(2C).HRMS(ES+)m/z calcd for C 21 H 25 N 3 O 2 S([M+H] + )384.1740,found 384.1745.
Example 2:
to a 10mL pressure tube was added 0.8mL of xylene, 0.089g (0.3 mmol) of 11-piperazinyldibenzo [ b, f ]][1,4]Sulphur nitrogen
0.032g (0.3 mmol) of diethylene glycol, 0.51mg (0.2 mol%) of bis (triphenylphosphine) carbonyl ruthenium dichloride monohydrate, stirring. Heating to 160 ℃, reacting for 10h, cooling to room temperature after the reaction is finished, distilling under reduced pressure to remove the solvent, adding 2mL of ethyl acetate into the residue, washing with water for 2 times, adding anhydrous magnesium sulfate for drying, filtering, distilling the filtrate under reduced pressure to remove the ethyl acetate, rapidly preparing liquid chromatograph for purification, collecting eluent containing the target product, and removing the eluent by reduced pressure distillation to obtain the 11- [4- [2- (2-hydroxyethoxy) ethyl-1-piperazinyl]]-dibenzo [ b, f ]][1,4]Sulphur nitrogen
Oil 0.104g. Yield: 90.4%, HPLC purity: 97.75 percent. HRMS (ES +) m/z calcd for C 21 H 25 N 3 O 2 S([M+H] + )384.1740,found 384.1745.
Example 3:
to a 10mL pressure tube was added 1mL of DMSO, 0.089g (0.3 mmol) of 11-piperazinyldibenzo [ b, f ]][1,4]Sulphur nitrogen
0.177g (1.7 mmol) of diethylene glycol,2.30mg (1 mol%) of bis (triphenylphosphine) carbonylacetonitrile and ruthenium dichloride were stirred. Heating to 140 ℃, reacting for 3h, cooling to room temperature after the reaction is finished, distilling off the solvent under reduced pressure, adding 2mL of ethyl acetate into the residue, washing with water for 2 times, adding anhydrous magnesium sulfate, drying, filtering, distilling off the ethyl acetate from the filtrate under reduced pressure, rapidly preparing liquid chromatograph for purification, collecting the eluent containing the target product, and distilling off the eluent by reduced pressure to obtain the 11- [4- [2- (2-hydroxyethoxy) ethyl-1-piperazinyl]]-dibenzo [ b, f ]][1,4]Sulphur nitrogen
0.014g of oil. Yield: 12.1%, HPLC purity: 98.05 percent. HRMS (ES +) m/z calcd for C 21 H 25 N 3 O 2 S([M+H] + )384.1740,found 384.1745.
Example 4:
to a 10mL pressure tube was added 1mL t-amyl alcohol, 0.089g (0.3 mmol) of 11-piperazinyldibenzo [ b, f ]][1,4]Sulphur nitrogen
0.106g (1.0 mmol) of diethylene glycol and 12.7mg (3 mol%) of tetrakis (triphenylphosphine) ruthenium dichloride are stirred. Heating to 150 ℃, reacting for 5h, cooling to room temperature after the reaction is finished, distilling off the solvent under reduced pressure, adding 2mL of ethyl acetate into the residue, washing with water for 2 times, adding anhydrous magnesium sulfate, drying, filtering, distilling off the ethyl acetate from the filtrate under reduced pressure, rapidly preparing liquid chromatograph for purification, collecting the eluent containing the target product, and distilling off the eluent by reduced pressure to obtain the 11- [4- [2- (2-hydroxyethoxy) ethyl-1-piperazinyl]]-dibenzo [ b, f ]][1,4]Sulphur nitrogen
Oil 0.09g. Yield: 8.1%, HPLC purity: 98.05 percent. HRMS (ES +) m/z calcd for C 21 H 25 N 3 O 2 S([M+H] + )384.1740,found 384.1745.
Example 5:
to a 10mL pressure tube was added 1mL t-amyl alcohol, 0.089g (0.3 mmol) of 11-piperazinyldibenzo [ b, f ]][1,4]Sulphur nitrogen
0.106g (1.0 mmol) of diethylene glycol, 2.30mg (1 mol%) of bis (triphenylphosphine) carbonylacetonitrile dichloride ruthenium were stirred. Heating to 120 ℃, reacting for 5h, cooling to room temperature after the reaction is finished, distilling under reduced pressure to remove the solvent, adding 2mL of ethyl acetate into the residue, washing with water for 2 times, adding anhydrous magnesium sulfate for drying, filtering, distilling the filtrate under reduced pressure to remove the ethyl acetate, rapidly preparing liquid chromatograph for purification, collecting eluent containing the target product, and removing the eluent by reduced pressure distillation to obtain the 11- [4- [2- (2-hydroxyethoxy) ethyl-1-piperazinyl]]-dibenzo [ b, f ]][1,4]Sulphur nitrogen
0.052g of oil. Yield: 45.5%, HPLC purity: 99.00 percent. HRMS (ES +) m/z calcd for C 21 H 25 N 3 O 2 S([M+H] + )384.1740,found 384.1745.
Claims (9)
1. A preparation method of quetiapine is characterized by comprising the following steps:
with 11-piperazinyl dibenzo [ b, f][1,4]Sulphur nitrogen
Reacting with diethylene glycol serving as a raw material in a ruthenium catalyst and an organic solvent at 120-160 ℃ for 3-10 h, and carrying out aftertreatment on the obtained reaction liquid to obtain the quetiapine; the ruthenium catalyst, diethylene glycol and 11-piperazinyl dibenzo [ b, f ]][1,4]Sulphur nitrogen
The amount ratio of the substances (A) is 0.02 to 0.05:1 to 5:1; the ruthenium catalyst is bis (triphenylphosphine) carbonyl acetonitrile and ruthenium dichloride or bis (triphenylphosphine) carbonyl ruthenium dichloride monohydrate;
the organic solvent is any one of toluene and xylene.
2. A process for preparing quetiapine as claimed in claim 1 wherein: the organic solvent is toluene.
3. A process for the preparation of quetiapine as claimed in claim 1 wherein: the organic solvent is mixed with 11-piperazinyl dibenzo [ b, f][1,4]Sulphur nitrogen
The mass ratio of (A) to (B) is 8-10: 1.
4. a process for the preparation of quetiapine as claimed in claim 3 wherein: the organic solvent is mixed with 11-piperazinyl dibenzo [ b, f ]][1,4]Sulphur nitrogen
The mass ratio of (A) to (B) is 10:1.
5. a process for the preparation of quetiapine as claimed in claim 1 wherein: the ruthenium catalyst is bis (triphenylphosphine) carbonyl acetonitrile and ruthenium dichloride.
6. A process for the preparation of quetiapine as claimed in claim 1 wherein: the reaction condition is that the reaction is carried out for 5 hours at 140 ℃.
7. A process for the preparation of quetiapine as claimed in claim 1 wherein: the ruthenium catalyst, diethylene glycol and 11-piperazinyl dibenzo [ b, f ]][1,4]Sulphur nitrogen
Is 0.03:3:1.
8. a process for the preparation of quetiapine as claimed in claim 1 wherein the post-treatment is: cooling the reaction liquid to room temperature, evaporating the solvent under reduced pressure, adding ethyl acetate for dissolving, washing, drying by anhydrous magnesium sulfate, filtering, evaporating the ethyl acetate under reduced pressure from the filtrate, purifying by using a rapid preparative liquid chromatograph, eluting by using a mixed solution of ethyl acetate and petroleum ether with a volume ratio of 2-20 as an eluent, collecting the eluent containing a target product, and distilling under reduced pressure to obtain quetiapine.
9. A process for the preparation of quetiapine as claimed in claim 8 wherein: the eluent is a mixed solution of ethyl acetate and petroleum ether with the volume ratio of 10.
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| JPH08311029A (en) * | 1995-03-10 | 1996-11-26 | Nissan Chem Ind Ltd | Alkylation of heteroaromatic amine |
| CN101619047A (en) * | 2009-08-17 | 2010-01-06 | 浙江苏泊尔制药有限公司 | Preparation process of quetiadine hemifumarate |
| CN102491949A (en) * | 2011-12-16 | 2012-06-13 | 南京理工大学 | Method for synthesizing 2-(N-alkyl) aminopyrimidine derivatives by means of N-alkylation |
| EP2966057B1 (en) * | 2013-03-04 | 2019-03-06 | Takasago International Corporation | Method for alkylation of amines |
| CN105859653B (en) * | 2016-04-29 | 2018-12-14 | 嘉兴学院 | A kind of synthetic method of Quetiapine |
| CA3058364A1 (en) * | 2017-03-31 | 2018-10-04 | Takasago International Corporation | Cationic ruthenium complex, and production method therefor and use thereof |
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