CN116675681A - Preparation method and application of Perilla Wo Leisheng intermediate - Google Patents

Preparation method and application of Perilla Wo Leisheng intermediate Download PDF

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CN116675681A
CN116675681A CN202310473883.7A CN202310473883A CN116675681A CN 116675681 A CN116675681 A CN 116675681A CN 202310473883 A CN202310473883 A CN 202310473883A CN 116675681 A CN116675681 A CN 116675681A
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formula
compound
suvorexant
acid
reaction
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陈磊
武滔
王端统
文望岳
梁峰
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Guangzhou Green Cross Pharmaceutical Co ltd
Guangdong Scientific Finder Pharmaceutical Technology Co ltd
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Guangzhou Green Cross Pharmaceutical Co ltd
Guangdong Scientific Finder Pharmaceutical Technology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • 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

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  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

The invention discloses a preparation method and application of a threo Wo Leisheng intermediate, and belongs to the technical field of chemical synthesis. The method takes the conventional materials as the starting point to directly synthesize, does not need to use the highly toxic butenone, has a simple synthetic route and does not depend on complex equipment; the Suvorax intermediate synthesized by the preparation method has higher purity and yield, the preparation of Suvorax by introducing the compound into a chiral center can simultaneously avoid the separation of chiral resolving agents or chiral HPLC and the chiral catalysis by using transition metals and biological enzymes, the production efficiency is high, and the obtained Suvorax intermediate can be directly applied to the preparation of Suvorax and is suitable for industrial mass production.

Description

Preparation method and application of Perilla Wo Leisheng intermediate
Technical Field
The invention relates to the technical field of chemical synthesis, in particular to a preparation method and application of a threo Wo Leisheng intermediate.
Background
Suvorexant, chemical name: [ (7R) -4- (5-chloro-1, 3-benzoxazol-2-yl) -7-methyl-1, 4-diazepan-1-yl ] [ 5-methyl-2- (2H-1, 2, 3-triazol-2-yl) phenyl ] methanone has the following structural formula:
suvorexant was first developed by moesadong (Merck Sharp Dohme, MSD), the first orexin receptor antagonist to effectively suppress wakefulness in humans by blocking the binding of orexin a and B to their receptors OX1R and OX2R, inhibiting orexin signaling system, and promoting and maintaining sleep, and thus has activity in the clinical treatment of insomnia, and is suitable for insomnia symptoms characterized by difficulty in falling asleep and/or maintaining sleep.
US7951797 discloses at the earliest a preparation method of su Wo Leisheng, the synthetic route is as follows:
the raw materials required by the synthetic route are easy to obtain, the reaction process is a classical organic reaction, but the defect is that a chiral HPLC separation treatment means is needed, the treatment process has multi-step amino protection and deprotection treatment, the operation procedures are more, the yield is lower, and the butenone serving as a starting material is a highly toxic product and is not suitable for industrial production.
US9108959 discloses another preparation method of suvorexant, the synthetic route is as follows:
the key chiral intermediate is prepared by adopting the traditional chiral resolution process in the synthetic route, so that complicated step procedures can be avoided, but the resolution yield of the chiral resolution process and the ee value of the final product in the synthetic route are low, further purification is required, and the total yield of the final product is only about 19%. In addition, the synthetic route adopts the thiophosgene and the butenone which have high toxicity and has extremely high restriction. Although CN 113929673a uses potassium ethylxanthate instead of thiophosgene on the basis of the technology, but still needs to use the highly toxic butenone, and meanwhile, in the process, although the scheme adopts a continuous flow reactor to improve the reaction safety, the equipment is expensive, and the cost performance of the whole synthetic route cannot be improved.
For a critical chiral intermediate of suvorexant, US9108959 discloses another method for preparing a critical chiral intermediate using a chiral ruthenium catalyst, the synthetic route is as follows:
however, the ruthenium catalyst used in this synthetic route is expensive and requires attention to heavy metal residues in API effective substances.
US9441254 discloses another preparation method of suvorexant, the synthetic route is as follows:
the synthesis route uses aminotransferase CDX-017 to catalyze amination and connects in series intramolecular ring closure reaction to construct chiral seven-membered diazacyclo, and the ee value is up to 99%. However, the intramolecular amination and ring closure reaction has more byproducts, so that the yield of the step is lower, and the highly toxic butenone is also used. Meanwhile, the raw material aminotransferase CDX-017 is not commercialized yet, and strong alkali LiHMDS used in the synthesis process is sensitive to water and air, and the limitation degree is high.
In summary, in the existing suvorexant synthesis route, chiral HPLC separation and chiral resolving agents are required, or chiral ruthenium catalysts and biological enzyme preparations are used for chiral catalysis, so that the process cost performance is low. Moreover, the existing synthetic route basically uses the highly toxic butenone, and the problem of safety cannot be effectively solved, so that commercial mass production is difficult to realize, and the production restriction is high.
Disclosure of Invention
Based on the defects existing in the prior art, the invention aims to provide a preparation method of a threo Wo Leisheng intermediate, which takes conventional materials as a starting point to directly synthesize without using a highly toxic butenone, and has a simple synthesis route and does not depend on complex equipment; the Suvorexant intermediate synthesized by the preparation method has higher purity and yield, the preparation of Suvorexant by introducing the compound into a chiral center can simultaneously avoid the separation of chiral resolving agents or chiral HPLC, and the chiral catalysis by using transition metals and biological enzymes, has high production efficiency, and is suitable for industrial mass production.
In order to achieve the above purpose, the invention adopts the following technical scheme:
a process for the preparation of a threo Wo Leisheng intermediate comprising the steps of:
(1) Carrying out one-stage reaction on the compound of the formula I and 2-aminoethanol to obtain a compound of the formula II;
(2) The compound of the formula II is subjected to a two-stage reaction to obtain a compound of the formula III;
(3) Carrying out three-stage reaction on the compound of the formula III and the compound of the formula IV to obtain a compound of the formula V;
(4) The compound of the formula V is subjected to four-stage reaction to obtain a compound of the formula VI, namely a suvorexant intermediate; the chemical structural formulas of the compounds of the formula I to the formula VI are as follows:
wherein the-O-P 1 comprising-O-Y, -O-SO 2 CH 3 、-O-SO 2 CF 3 、-OTs、-OBs、-O-CH 2 OCH 3 、-O-C(CH 3 ) 3 、-O-CH 2 Ph、-O-p-methoxybenzyl(PMB)、-OTMS、-OTES、-OTBDMS、-OTBDPS、-OTIPS、-O-CPh 3 At least one of (a) and (b);
P 2 comprises at least one of tert-butyloxycarbonyl, benzyloxycarbonyl, benzyl, p-methoxybenzyl, 9-fluorenylmethoxycarbonyl, 2-biphenyl-2-propoxycarbonyl, phthalimido, p-toluenesulfonyl, trityl, trifluoroacetyl, formyl, acetyl, allyl, 4-nitrobenzyl, 2-methylbenzyl, 4-chlorobenzyl or 3-fluorobenzyl;
-O-P 3 comprising-O-Y, -O-SO 2 CH 3 、-O-SO 2 CF 3 、-OTs、-OBs、-O-CH 2 OCH 3 、-O-C(CH 3 ) 3 、-O-CH 2 Ph、-O-p-methoxybenzyl、-OTMS、-OTES、-OTBDMS、-OTBDPS、-OTIPS、-O-CPh 3 At least one of (a) and (b);
the X comprises at least one of halogen, methoxy and ethoxy; y comprises halogen.
Preferably, the said-O-P 1 comprising-O-Y, -O-SO 2 CH 3 -at least one of OTs, said Y being halogen.
Preferably, the P 2 Including at least one of t-butoxycarbonyl, benzyloxycarbonyl, benzyl and p-methoxybenzyl.
Preferably, the said-O-P 3 comprising-O-Y, -O-SO 2 CH 3 -at least one of OTs, said Y being halogen.
The synthetic route of the suvorexant intermediate (i.e., the compound of formula VI) of the present invention is as follows:
compared with the prior art, the preparation method can avoid the use of highly toxic materials, especially common butenone, in the preparation stage, and the compound of the formula IV is introduced into a chiral center (the compound can be directly synthesized by using a conventional material (R) -3-aminobutanol) as a starting material), so that the separation of chiral resolving agent or chiral HPLC is avoided, the chiral catalysis by using transition metal and biological enzyme is avoided, an expensive continuous flow reactor is not required, the reaction operation is simple, the material cost is low, the product is easy to separate and purify, the yield is high, and the method is suitable for industrial scale production.
Preferably, the first-stage reaction is a substitution reaction, the substitution reaction is catalyzed by a catalyst in a solvent, the solvent is at least one of tetrahydrofuran, acetonitrile, dichloromethane, dimethylformamide, dimethylacetamide, cyclohexane and n-hexane, and the catalyst is at least one of acetic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid and citric acid.
More preferably, when X is at least one of methoxy and ethoxy, the catalyst is an acid catalyst, and the acid catalyst is at least one of acetic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, and citric acid; when X is halogen, the catalyst is an alkaline catalyst, and the alkaline catalyst is at least one of triethylamine, 1,8 diazabicyclo (5.4.0) undec 7 ene, N-diisopropylethylamine, 4-dimethylaminopyridine, N-methylmorpholine, piperidine, pyridine, N-methylpiperazine, sodium bicarbonate, potassium carbonate, sodium hydroxide, cesium carbonate and sodium phosphate.
More preferably, the solvent is at least one of tetrahydrofuran, dichloromethane and cyclohexane, the acid catalyst is at least one of acetic acid, trifluoroacetic acid and phosphoric acid, and the basic catalyst is at least one of triethylamine, 1,8 diazabicyclo (5.4.0) undec 7 ene, N-diisopropylethylamine and sodium bicarbonate. .
Preferably, the two-stage reaction is a substitution reaction, the substitution reaction is carried out in a solvent through the reaction of a compound shown in a formula II and a reaction reagent A under the action of a basic catalyst, the solvent is at least one of dichloromethane, toluene, xylene, ethyl acetate, isopropyl acetate, acetonitrile, tetrahydrofuran, dimethylformamide, dimethylacetamide and acetone, the basic reagent is at least one of triethylamine, 1,8 diazabicyclo (5.4.0) undec 7 ene (DBU), N-Diisopropylethylamine (DIPEA), 4-Dimethylaminopyridine (DMAP), N-methylmorpholine, piperidine, pyridine, N-methylpiperazine, sodium bicarbonate, potassium carbonate, sodium hydroxide, cesium carbonate and sodium phosphate, and the reaction reagent A is at least one of phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, p-toluenesulfonyl chloride, methanesulfonyl chloride and trifluoromethanesulfonyl chloride.
The hydroxyl groups in the compounds of formula II may be protected by the above-mentioned halogenating agents or hydroxyl protecting agents and are not reacted or removed in subsequent reactions.
Preferably, the three-stage reaction is an alkylation reaction carried out by reacting a compound of formula III with a compound of formula IV in a solvent which is at least one of dichloromethane, toluene, xylene, ethyl acetate, isopropyl acetate, acetonitrile, tetrahydrofuran, N-Dimethylformamide (DMF), acetone.
More preferably, the solvent is at least one of dichloromethane, toluene, xylene, ethyl acetate.
More preferably, the solvent further contains a catalyst, and the catalyst is at least one of triethylamine, 1,8 diazabicyclo (5.4.0) undec 7 ene (DBU), N-Diisopropylethylamine (DIPEA), 4-Dimethylaminopyridine (DMAP), N-methylmorpholine, piperidine, pyridine, N-methylpiperazine, sodium bicarbonate, potassium carbonate, sodium hydroxide, cesium carbonate, sodium phosphate and ammonium bicarbonate.
Preferably, the four-stage reaction comprises the steps of: firstly, carrying out an amino protecting group removal reaction on a compound of a formula V and a reaction reagent B in a solvent, dissolving the obtained intermediate product in an alkaline organic solvent, carrying out a condensation reaction, and finally, carrying out a reaction with concentrated hydrochloric acid in a salifying solvent to obtain a compound of a formula VI; the reactant B is hydrochloric acid, trifluoroacetic acid, formic acid, hydrobromic acid, hydrazine and Pd (OH) 2 /C, pd/C and PdCl 2 At least one of the groups/C,
more preferably, the amino protecting group removal reaction is carried out using a solvent selected from the group consisting of methylene chloride, toluene, xylene, ethyl acetate, isopropyl acetate, acetonitrile, tetrahydrofuran, dimethylformamide, dimethylacetamide, acetone, and C 1 -C 4 At least one of lower alcohols, more preferably at least one of dichloromethane, toluene, xylene, ethyl acetate.
It should be noted that when reactant B itself is a hydrogen source, the amino protecting group removal reaction may not require the introduction of an additional hydrogen source, whereas when reactant B is a metal reagent, such as Pd (OH) 2 /C, pd/C and/or PdCl 2 at/C, a hydrogen source, such as hydrogen, is introduced into the solvent to effect the amino protecting group removal reaction.
More preferably, the basic organic solvent comprises a base and an organic solvent selected from the group consisting of dichloromethane, toluene, xylene, ethyl acetate, isopropyl acetate, acetonitrile, tetrahydrofuran, dimethylformamide, dimethylacetamide, acetone, C 1 -C 4 At least one of lower alcohols, wherein the base is at least one of triethylamine, 1,8 diazabicyclo (5.4.0) undec 7 ene (DBU), N-Diisopropylethylamine (DIPEA), 4-Dimethylaminopyridine (DMAP), N-methylmorpholine, piperidine, pyridine, N-methylpiperazine, sodium bicarbonate, potassium carbonate, sodium hydroxide, cesium carbonate and sodium phosphate.
More preferably, the salt-forming solvent is at least one of a mixture of dimethylacetamide and toluene, a mixture of dimethylacetamide and acetone, dimethylacetamide, a mixture of acetone and water, a mixture of N, N-dimethylformamide and toluene, a mixture of N, N-dimethylformamide and acetone, and water.
Another object of the invention is to provide the use of the process for the preparation of the intermediate of suvorexant in the preparation of suvorexant.
Still another object of the present invention is to provide a method for preparing su Wo Leisheng, comprising the steps of:
the suvorexant intermediate of the invention is subjected to condensation reaction with a compound of formula VII to obtain suvorexant.
Preferably, the condensation reaction is carried out with a chlorinating agent in a solvent comprising at least one of dichloromethane, toluene, xylene, ethyl acetate, isopropyl acetate, acetonitrile, tetrahydrofuran, dimethylformamide, dimethylacetamide, acetone under the action of a catalyst.
The Suwhatsoever intermediate prepared by the preparation method of the Suwhatsoever intermediate has high purity, can directly generate condensation reaction with the compound of the formula VII under the solvent condition according to the following synthetic route to generate Suwhatsoever without adopting special equipment, and has good application prospect.
The invention has the beneficial effects that the invention provides a preparation method of the intermediate of the Perilla Wo Leisheng, which takes the conventional materials as the starting point to directly synthesize without using the highly toxic butenone, and has simple synthetic route and does not depend on complex equipment; the Suvorax intermediate synthesized by the preparation method has higher purity and yield, the preparation of Suvorax by introducing the compound into a chiral center can simultaneously avoid the separation of chiral resolving agents or chiral HPLC and the chiral catalysis by using transition metals and biological enzymes, the production efficiency is high, and the obtained Suvorax intermediate can be directly applied to the preparation of Suvorax and is suitable for industrial mass production.
Drawings
FIG. 1 is a nuclear magnetic pattern of a suvorexant intermediate prepared in example 1 of the present invention;
FIG. 2 is a chart showing the detection of the enantiomer content of the intermediate of Suvorexant prepared in example 1 of the present invention;
FIG. 3 is a liquid chromatogram of a suvorexant intermediate prepared in example 1 of the present invention;
FIG. 4 is a nuclear magnetic spectrum of Suvorexant prepared in practical example 1 of the present invention;
FIG. 5 is a chart showing the measurement of the enantiomer content of Suvorexant prepared in practical example 1 of the present invention;
FIG. 6 is a liquid chromatogram of Suvorexant prepared in practical example 1 of the present invention.
Detailed Description
The present invention will be further described with reference to specific examples and comparative examples for better illustrating the objects, technical solutions and advantages of the present invention, and the object of the present invention is to be understood in detail, not to limit the present invention. All other embodiments, which can be made by those skilled in the art without the inventive effort, are intended to be within the scope of the present invention. The experimental reagents, raw materials and instruments designed in the practice and comparative examples of the present invention are common reagents, raw materials and instruments unless otherwise specified.
Meanwhile, it should be noted that, due to the requirement of actual production efficiency and convenience, a plurality of parallel batches actually exist in each step of the preparation method in each embodiment, the preparation conditions and the preparation results of each parallel batch are almost the same, in order to ensure production and accelerate production efficiency, the products of each parallel batch are mixed or matched, for example, the preparation raw material used in the step (2) in the embodiment 1 shown in the invention is not only derived from the product obtained in a specific reaction vessel in the step (1), but reasonably distributed in a plurality of parallel batches according to the actual requirement, for example, the mass of [2- [ (5-chloro-benzoxazol-2-yl) (R-3-benzyloxycarbonyl) amino ] butyl ] -chloroethane obtained in the step (3) is 37.06g, in order to ensure production requirement and facilitate the calculation of the batching molar ratio in production, the similar products with similar purity and yield are prepared in the parallel batches and are mixed to 43.63g and applied in the reaction in the step (4), but the purity and yield of the product recorded in the step (1) are almost the same, and the result of each parallel batch is repeated to represent only one of the parallel batches. It should be appreciated by those skilled in the art that in the case where each step is relatively independent and the production conditions of the parallel batches are close, such a treatment does not affect the judgment of the preparation quality and the preparation efficiency of the preparation method.
Example 1
An embodiment of the preparation method of the suvorexant intermediate of the present invention comprises the following steps:
(1) In a 500mL reaction bottle at room temperature, 19.76g of a compound of formula I, namely 5-chloro-2-ethoxy-benzoxazole, and 7.20g of 2-amino ethanol are mixed in 200mL of cyclohexane, 0.8g of acetic acid is added, the mixture is heated, refluxed and stirred for 14h for substitution reaction, the mixture is cooled and cooled to 20 ℃, filtered, and the obtained filter cake is washed by cyclohexane and dried to obtain 19.35g of a compound of formula II, namely 2- [ (5-chloro-1, 3-benzoxazol-2-yl) amino ] ethanol, and the purity of the detected product is 99.2 percent, and the yield is 91 percent;
(2) The compound of formula II 2- [ (5-chloro-1, 3-benzoxazol-2-yl) amino group is placed in a 500mL reaction flask at room temperature]Ethanol 21.26g, N-Diisopropylethylamine (DIPEA) 18.50g and PCl 3 Mixing in 200mL of xylene and substitution reaction at 20℃for 10h, followed by addition of 100mL of water, separation of the organic phase and concentration of the resulting oil at 45℃under reduced pressure, afforded 19.63g of the compound of formula III 5-chloro-N- (2-chloroethyl) -1, 3-benzoxazol-2-amino in 85% yield and 98% purity;
(3) In a 1L reaction flask, 23.11g of 5-chloro-N- (2-chloroethyl) -1, 3-benzoxazol-2-amino group of the compound of formula III and 45.20g of (3R) -3- [ (2-methylpropylamine-2-yl) benzyloxycarbonylamino) butyl-methanesulfonate of the compound of formula IV are added to 300mL of tetrahydrofuran at room temperature, 26.5g of ammonium bicarbonate is added and heated to 70℃and stirred for 8 hours for alkylation reaction, the temperature is lowered to room temperature, 200mL of water is added, the organic phase is separated and the obtained oil is concentrated under reduced pressure at 55℃to obtain 37.06g of the compound of formula V [2- [ (5-chloro-benzoxazol-2-yl) (R-3-benzyloxycarbonyl) amino ] butyl ] -chloroethane with a yield of 85% purity of 96%;
(4) Compounds of formula V [2- [ (5-chloro-benzooxazol-2-yl) (R-3-benzyloxycarbonyl) amino ] are placed in a 1L reaction flask at room temperature]Butyl group]43.63g of chloroethane is mixed with 1.50g of 10wt% Pd/C in 500mL of isopropanol, then hydrogen is introduced into the mixture and stirred for reaction for 6h, the obtained filtrate is filtered, after concentrating under reduced pressure at 45 ℃, 500mL of ethyl acetate and 23.8g of sodium bicarbonate are added, heating is carried out to 50 ℃ and stirring is carried out for reaction for 10h, cooling is carried out to room temperature, then 200mL of water is added, the organic phase is separated and concentrated under reduced pressure at 45 ℃, and the obtained oily phase is obtainedAdding 100mL of N, N-dimethylacetamide, 250mL of acetone and 10g of water, uniformly mixing, cooling to 0 ℃, dropwise adding 102.6g of concentrated hydrochloric acid, continuously stirring for 2 hours, filtering, washing and drying the obtained filter cake to obtain a white solid compound of formula VI, namely 5-chloro-2- ((R) -5-methyl- [1,4]Diazacycloheptan-1-yl) benzoxazole hydrochloride 23.55g, which is a suvorexant intermediate; yield 78%, purity more than 99.8%, ee value more than 99.5%, 1 H NMR(500MHz,MeOD):δ7.34(d,J＝8.5Hz,1H),7.29(d,J＝2.1Hz,1H),7.07(dd,J＝8.5,2.1Hz,1H),4.12-3.99(m,3H),3.83-3.77(m,1H),3.67-3.56(m,2H),3.45-3.39(m,1H),2.28-2.24(m,1H),2.20-2.11(m,1H),1.46(d,J＝6.7Hz,3H).MS(ESI)m/z([M+H] + ) 266.11. The nuclear magnetic resonance spectrum, the enantiomer content detection spectrum (detection chromatographic column: xylonite CHIRALPAK AD-H, wherein the spectrum code Su205 is a Suvorexant intermediate, and the Su205 isomer is an enantiomer) and the liquid chromatography (detection chromatographic column: horizon C18, wherein the spectrum code Su205 is a Suvorexant intermediate) are shown in figures 1-3.
The chemical structural formulas of the compounds of the formula I to the formula VI are as follows:
example 2
An embodiment of the preparation method of a suvorexant intermediate according to the present invention, wherein the detection data of the suvorexant intermediate prepared in the embodiment is the same as that of embodiment 1, and the difference between the detection data and embodiment 1 is that the step (1) is: 18.80g of the compound of formula I, 2, 5-dichlorobenzoxazole and 7.60g of 2-aminoethanol were mixed in a 500mL reaction flask at room temperature, 15.60g of triethylamine was added thereto, the reaction was stirred for 6 hours to carry out substitution reaction, 200mL of water was added thereto, filtration was carried out, and the obtained cake was washed with water and dried to obtain 18.92g of the compound of formula II, 2- [ (5-chloro-1, 3-benzoxazol-2-yl) amino ] ethanol, the purity of which was detected to be 98.8%, and the yield was 89%. The structure of the compound of the formula I is as follows:
example 3
An embodiment of the preparation method of the suvorexant intermediate of the present invention, the detection data of the suvorexant intermediate prepared in the embodiment is almost the same as that of the embodiment 1, and the method comprises the following steps:
(1) Step (1) is the same as in example 1;
(2) 21.26g of the compound of formula II, 2- [ (5-chloro-1, 3-benzoxazol-2-yl) amino ] ethanol, 15.25g of triethylamine and 22.80g of p-toluenesulfonyl chloride are mixed in 200mL of xylene at room temperature in a 500mL reaction flask and substitution-reacted at 10℃for 6h, then 100mL of water is added, the organic phase is separated and the resulting oil is concentrated under reduced pressure at 45℃to give 31.54g of the compound of formula III, 2- [ (5-chloro-1, 3-benzoxazol-2-yl) amino ] ethanol-4-methylbenzenesulfonate in 86% yield and purity 95%;
(3) 36.68g of the compound of formula III 2- [ (5-chloro-1, 3-benzoxazol-2-yl) amino ] ethanol-4-methylbenzenesulfonate and 41.16g of the compound of formula IV (3R) -3- [ (2-methylpropanamine-2-yl) tert-butoxycarbonylamino) butyl-4-methylbenzenesulfonate are added to 400mL of toluene at room temperature in a 1L reaction flask, 14.25g of triethylamine is then added and heated to 80℃with stirring for 6 hours for alkylation, the temperature is reduced to room temperature, 200mL of water are added, the organic phase is separated and the resulting oil is concentrated under reduced pressure at 55℃to give 48.42g of the compound of formula V [2- [ (5-chloro-benzoxazol-2-yl) (R-3-tert-butoxycarbonyl) amino ] butyl ] -4-methylbenzenesulfonate with a yield of 90% purity of 96%;
the preparation method of the compound (3R) -3- [ (2-methylpropylamine-2-yl) tert-butoxycarbonylamino) butyl-4-methylbenzenesulfonate shown in the formula IV comprises the following steps: 17.83g of (R) -3-aminobutanol, 24.25g of triethylamine and 52.32g of di-tert-butyl dicarbonate are added into 200mL of methylene dichloride at room temperature in a reaction bottle, stirring is carried out for 4h, then 100mL of water is added, an organic phase is separated into another reaction bottle, 24.25g of triethylamine and 45.80g of p-toluenesulfonyl chloride are added, the temperature is reduced to 10 ℃ for stirring and reacting for 6h, 100mL of water is added, the organic phase is separated and concentrated under reduced pressure at 45 ℃ to obtain 60.44g of compound (3R) -3- [ (2-methylpropylamine-2-yl) tert-butoxycarbonylamino) butyl-4-methylbenzenesulfonate with the purity of 98.9 percent and the yield of 88 percent;
(4) 43.63g of the compound [2- [ (5-chloro-benzooxazol-2-yl) (R-3-tert-butoxycarbonyl) amino ] butyl ] -4-methylbenzenesulfonate of the formula V is mixed with 100mL of concentrated hydrochloric acid in 500mL of toluene at room temperature in a 1L reaction bottle and stirred for reaction for 6h, 200mL of water is added, 15.68g of triethylamine is added into an organic phase after separation, the organic phase is heated to 80 ℃ for reaction for 10h, the temperature is reduced to room temperature, then 200mL of water is added, the organic phase is separated and concentrated under reduced pressure at 55 ℃, 150mL of N, N-dimethylacetamide and 400mL of toluene are added into the obtained oil, the mixture is uniformly mixed and reduced to 10 ℃, 102.6g of concentrated hydrochloric acid is added dropwise, stirring is continued for 2h, filtering is carried out, and the obtained filter cake is washed and dried to obtain 22.65g of white solid 5-chloro-2- ((R) -5-methyl- [1,4] diazepan-1-yl) benzooxazol hydrochloride of the compound of the formula VI, namely the suvorexant intermediate; the yield is 75%, the purity is more than 99.8%, and the ee value is more than 99.5%.
The chemical structural formulas of the compounds of the formula I to the formula VI are as follows:
example 4
An embodiment of the preparation method of the suvorexant intermediate of the present invention, the detection data of the suvorexant intermediate prepared in the embodiment is almost the same as that of the embodiment 1, and the method comprises the following steps:
(1) Step (1) is the same as in example 1;
(2) 21.26g of 2- [ (5-chloro-1, 3-benzoxazol-2-yl) amino ] ethanol, 22.50g of 1,8 diazabicyclo (5.4.0) undec 7 ene and 13.68g of methanesulfonyl chloride of the compound of formula II are mixed in 200mL of toluene at room temperature in a 500mL reaction flask and reacted for 4h with substitution at 0℃followed by addition of 100mL of water, separation of the organic phase and concentration of the resulting oil under reduced pressure at 60℃to give 25.87g of 2- [ (5-chloro-1, 3-benzoxazol-2-yl) amino ] ethanol-methanesulfonate of the compound of formula III in 89% yield, purity 96%;
(3) 29.07g of 2- [ (5-chloro-1, 3-benzoxazol-2-yl) amino ] ethanol-methanesulfonate, which is the compound of formula III, and 40.16g of (3R) -3- [ (2-methylpropan-2-yl) tert-butoxycarbonylamino) butyl-4-methylbenzenesulfonate, which is the compound of formula IV, are added to 300mL of methylene chloride at room temperature in a 1L reaction flask, 16.80g of N, N-diisopropylethylamine is added and heated to 50 ℃ and stirred for 4 hours for alkylation reaction, cooled to room temperature, 200mL of water is added, the organic phase is separated and the resulting oil is concentrated under reduced pressure at 55 ℃ to give 42.50g of ethyl [2- [ (5-chloro-benzoxazol-2-yl) (R-3-tert-butoxycarbonyl) amino ] butyl ] -methanesulfonate, which is the compound of formula V, yield 92% purity is 97%;
(4) 46.20g of the compound of formula V [2- [ (5-chloro-benzooxazol-2-yl) (R-3-tert-butoxycarbonyl) amino ] butyl ] -methanesulfonic acid ethyl ester is mixed with 22.80g of trifluoroacetic acid in 500mL of ethyl acetate at room temperature and heated to 40 ℃ for stirring reaction for 6h, 200mL of water is added, 20.80g of N, N-diisopropylethylamine is added to the organic phase after separation, heating to 60 ℃ for stirring reaction for 10h, cooling to room temperature, 200mL of water is then added, the organic phase is separated and concentrated at 55 ℃, 100mL of N, N-dimethylformamide and 200mL of acetone are added to the obtained oil, the mixture is uniformly mixed and cooled to 10 ℃, after 102.6g of concentrated hydrochloric acid is added dropwise, stirring is continued for 2h, filtering is carried out, and 25.06g of 5-chloro-2- ((R) -5-methyl- [1,4] diazepan-1-yl) benzooxazol hydrochloride of the formula VI is obtained as a white solid after washing and drying, namely, the intermediate is prepared; yield 83%, purity > 99.8%, ee value > 99.5%.
The chemical structural formulas of the compounds of the formula I to the formula VI are as follows:
example 5
An embodiment of the preparation method of a suvorexant intermediate according to the present invention, wherein the detection data of the suvorexant intermediate prepared in the embodiment is almost the same as that of embodiment 3, and the difference from embodiment 3 is that the step (3) is as follows:
(3) 36.68g of the compound of formula III 2- [ (5-chloro-1, 3-benzoxazol-2-yl) amino ] ethanol-4-methylbenzenesulfonate and 40.16g of the compound of formula IV (3R) -3- [ (2-methylpropan-2-yl) tert-butoxycarbonylamino) butyl-methanesulfonate are added to 400mL of xylene at room temperature in a 1L reaction flask, 20.50g of 1,8 diazabicyclo (5.4.0) undec-7-ene is subsequently added and heated to 80℃and stirred for 6h for alkylation, cooled to room temperature, 200mL of water are added, the organic phase is separated and the resulting oil is concentrated under reduced pressure at 55℃to give 46.27g of the compound of formula V [2- [ (5-chloro-benzoxazol-2-yl) (R-3-tert-butoxycarbonyl) amino ] butyl ] -4-methylbenzenesulfonate in 86% yield 96% purity;
22.63g of the obtained 5-chloro-2- ((R) -5-methyl- [1,4] diazepan-1-yl) benzoxazole hydrochloride as a compound of the formula VI is a suvorexant intermediate; the yield is 74.8%, the purity is more than 99.8%, and the ee value is more than 99.5%.
The chemical structural formulas of the compound of the formula III and the compound of the formula IV are as follows:
example 6
An embodiment of the preparation method of the suvorexant intermediate of the present invention, the detection data of the suvorexant intermediate prepared in the embodiment is almost the same as that of embodiment 3, and the method comprises the following steps:
(1) Step (1) is the same as in example 3;
(2) Step (2) is the same as in example 3;
(3) 36.68g of the compound of formula III 2- [ (5-chloro-1, 3-benzoxazol-2-yl) amino ] ethanol-4-methylbenzenesulfonate and 38.56g of the compound of formula IV (3R) -3- [ (2-methylpropan-2-yl) benzylamino) butyl-methanesulfonate are added to 400mL of ethyl acetate at room temperature in a 1L reaction bottle, 25.50g of sodium carbonate is then added and heated to 80 ℃ and stirred for 6h for alkylation reaction, the temperature is reduced to room temperature, 200mL of water is added, the organic phase is separated and the obtained oil is concentrated under reduced pressure at 55 ℃ to obtain 47.00g of the compound of formula V [2- [ (5-chloro-benzoxazol-2-yl) (R-3-benzyl) amino ] butyl ] -4-methylbenzenesulfonate, the yield is 89%, and the purity is 97%;
(4) 52.80g of the compound of formula V [2- [ (5-chloro-benzooxazol-2-yl) (R-3-benzyl) amino ] butyl ] -4-methylbenzenesulfonic acid ethyl ester is mixed with 2.65g of 10wt% Pd/C in 500mL of methanol at room temperature, the obtained mixture is introduced with hydrogen and stirred for 6h, filtration is carried out, the obtained filtrate is concentrated under reduced pressure at 45 ℃, 500mL of dichloromethane and 22.80g of 1, 8-diazabicyclo (5.4.0) undec 7 alkene are added into the obtained concentrate, the mixture is heated to 40 ℃ for 8h with stirring, the temperature is reduced to room temperature, then 200mL of water is added, the organic phase is separated and concentrated under reduced pressure at 55 ℃, 100mL of N, N-dimethylacetamide and 250mL of acetone are added into the mixture, after uniform mixing and cooling to 0 ℃, 102.6g of concentrated hydrochloric acid are added dropwise, the mixture is continuously stirred for 2h, filtration is carried out, and the obtained filter cake is dried, thus obtaining white solid-state 5-chloro-2- ((R) -5-methyl- [1,4] diazabicyclo (5.0) 1-benzooxazol-1-yl) hydrochloride which is prepared as a hydrochloride intermediate, 25g of m-hydrochloric acid; the yield is 86%, the purity is more than 99.8%, and the ee value is more than 99.5%.
The chemical structural formulas of the compounds of the formula I to the formula VI are as follows:
example 7
An embodiment of the preparation method of a suvorexant intermediate according to the present invention, wherein the detection data of the suvorexant intermediate prepared in the embodiment is almost the same as that of embodiment 3, and the difference from embodiment 3 is only that the step (4) is:
(4) 53.81g of the compound of formula V [2- [ (5-chloro-benzooxazol-2-yl) (R-3-tert-butoxycarbonyl) amino ] butyl ] -4-methylbenzenesulfonate in 500mL of dichloromethane is mixed with 22.80g of trifluoroacetic acid and heated to 50 ℃ for stirring reaction for 6h at room temperature, 200mL of water is added, 22.80g of 1,8 diazabicyclo (5.4.0) undec-7 ene is added into the organic phase after separation, stirring reaction is carried out for 8h at 70 ℃ after the organic phase is added, cooling to room temperature, 200mL of water is then added, the organic phase is separated and concentrated at 55 ℃, 80mL of N, N-dimethylacetamide and 200mL of toluene are added into the obtained oil, the mixture is uniformly mixed and cooled to 10 ℃, 102.6g of concentrated hydrochloric acid are added dropwise, stirring is continued for 2h, and the obtained filter cake is washed and dried to obtain 24.70g of 5-chloro-2- ((R) -5-methyl- [1,4] diazacycloheptan-1-yl) benzooxazol salt of the compound of formula VI in the form of white solid, namely, the intermediate hydrochloride; the yield is 82%, the purity is more than 99.8%, and the ee value is more than 99.5%.
Example 8
In one example of the preparation method of the suvorexant intermediate, the detection data of the suvorexant intermediate prepared in the example is almost the same as that of the example 1, 40.23g of the compound [2- [ (5-chloro-benzooxazol-2-yl) (R-3-tert-butoxycarbonyl) amino ] butyl ] -chloroethane of the formula V obtained by the method of the invention is mixed with 24.80g of trifluoroacetic acid in 500mL of dichloromethane and heated to 30 ℃ for stirring reaction for 8 hours, 200mL of water is added, 20.80g of N, N-diisopropylethylamine is added in an organic phase after separating an organic phase, the mixture is heated to 60 ℃ for stirring reaction for 10 hours, then 200mL of water is added, the organic phase is separated and concentrated at 55 ℃ under reduced pressure, 80mL of N, N-dimethylacetamide and 200mL of toluene are added, the mixture is uniformly mixed and cooled to 10 ℃, after dropwise adding 102.6g of concentrated hydrochloric acid, the mixture is continuously stirred for 2 hours, the mixture is filtered, and the obtained filter cake is washed and dried, thus obtaining a white solid compound of the formula VI, namely 5-chloro-2-methyl- [1,4] benzooxazol 1, 1 ] in the form of the m-1-phase, 1-naphthas the hydrochloride; the yield is 63%, the purity is more than 99.8%, and the ee value is more than 99.5%.
The chemical structural formula of the compound of the formula V is as follows:
example 9
An example of a process for preparing a suvorexant intermediate according to the present invention, the example preparingThe measurement data of the Suvorexant intermediate (Suvorexant) was nearly identical to those of example 1, and the compound of formula V [2- [ (5-chloro-benzooxazol-2-yl) (R-3-benzyloxycarbonyl) amino group obtained by the method of the present invention]Butyl group]49.60g of ethyl methanesulfonate with 2.50g of 10wt% Pd (OH) in 500mL of ethanol in a 1L autoclave 2 mixing/C, introducing hydrogen gas, stirring and reacting for 6h, filtering, concentrating the obtained filtrate under reduced pressure at 45 ℃, adding 500mL of ethyl acetate and 22.80g of sodium carbonate into the concentrate, and then stirring and reacting for 10h at 70 ℃. Adding 200mL of water into the obtained mixed solution, separating an organic phase, concentrating under reduced pressure at 45 ℃, adding 100mL of N, N-dimethylacetamide, 250mL of acetone and 15g of water, uniformly mixing, cooling to 0 ℃, dropwise adding 102.6g of concentrated hydrochloric acid, continuously stirring for 2 hours, filtering, washing and drying the obtained filter cake to obtain a white solid compound of formula VI, namely 5-chloro-2- ((R) -5-methyl- [1,4]Diazepan-1-yl) benzoxazole hydrochloride 25.36g, namely the suvorexant intermediate; the yield is 84%, the purity is more than 99.8%, and the ee value is more than 99.5%.
The chemical structural formula of the compound of the formula V is as follows:
practical example 1
The suvorexant intermediate obtained in example 1 was used for the preparation of suvorexant, and the preparation steps were as follows:
17.60g of 5-methyl-2- (2H-1, 2, 3-triazol-2-yl) benzoic acid, 150mL of methylene chloride and 1.70g of DMF are mixed at room temperature in a 100mL single-port bottle, the obtained mixture is cooled to 0-5 ℃, 15.65g of oxalyl chloride is slowly added dropwise, the mixture is reacted for 1H at 25 ℃ after the completion of the dropwise addition, the mixture is concentrated under reduced pressure, 300mL of methylene chloride is added and stirred until the mixture is dissolved, and 25.10g of 5-chloro-2- ((R) -5-methyl- [1,4] diazepan-1-yl) benzoxazole hydrochloride and 25.18g of triethylamine are added and the mixture is reacted for 1H at 15 ℃. To the resulting mixture was added 300mL of water, and the organic phase was separated and concentrated to dryness under reduced pressure at 50 ℃. 100mL of water and 200mL of absolute ethyl alcohol are added into the obtained concentrate, the temperature is raised to 80 ℃ to enable oily matters to be completely dissolved, then the temperature is slowly reduced to room temperature, crystallization is carried out for 2 hours, filtration is carried out, a filter cake is washed by 50mL of ethyl alcohol, and after vacuum drying at 55 ℃, 32.20g of white solid is obtained, namely, suvorexant, the yield is 86%, the purity is 99.95%, and the ee value is more than 99.5%.
1 H-NMR(CDCl 3 ,400MHz)δ7.90-7.66(m,3H),7.31-6.96(m,5H),4.55(d,J＝14.1Hz,1H),4.23-3.07(m,6H),2.41(m,4H),1.86-1.53(m,1H),1.30-1.14(m,3H).MS(ESI)m/z([M+H] + )451.16。
The obtained nuclear magnetic spectrum, enantiomer content detection spectrum (detection chromatographic column: cellophane CHIRALPAK AD-H, wherein the spectrum code Su is suvorexant, and the Su isomer is enantiomer) and liquid chromatography (detection chromatographic column: horizon C18, wherein the spectrum code Su is suvorexant) of Suvorexant are shown in fig. 4-6.
Similarly, the suvorexant intermediate obtained in other examples was prepared according to the above-described method, and the results were similar.
Finally, it should be noted that the above embodiments are only for illustrating the technical solution of the present invention and not for limiting the scope of the present invention, and although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that the technical solution of the present invention may be modified or substituted equally without departing from the spirit and scope of the technical solution of the present invention.

Claims (10)

1. A process for the preparation of a threo Wo Leisheng intermediate comprising the steps of:
(1) Carrying out one-stage reaction on the compound of the formula I and 2-aminoethanol to obtain a compound of the formula II;
(2) The compound of the formula II is subjected to a two-stage reaction to obtain a compound of the formula III;
(3) Carrying out three-stage reaction on the compound of the formula III and the compound of the formula IV to obtain a compound of the formula V;
(4) The compound of the formula V is subjected to four-stage reaction to obtain a compound of the formula VI, namely a suvorexant intermediate;
the chemical structural formulas of the compounds of the formula I to the formula VI are as follows:
wherein the-O-P1 comprises-O-Y, -O-SO 2 CH 3 、-O-SO 2 CF 3 、-OTs、-OBs、-O-CH 2 OCH 3 、-O-C(CH 3 ) 3 、-O-CH 2 Ph、-O-p-methoxybenzyl、-OTMS、-OTES、-OTBDMS、-OTBDPS、-OTIPS、-O-CPh 3 At least one of (a) and (b);
P 2 comprises at least one of tert-butyloxycarbonyl, benzyloxycarbonyl, benzyl, p-methoxybenzyl, 9-fluorenylmethoxycarbonyl, 2-biphenyl-2-propoxycarbonyl, phthalimido, p-toluenesulfonyl, trityl, trifluoroacetyl, formyl, acetyl, allyl, 4-nitrobenzyl, 2-methylbenzyl, 4-chlorobenzyl or 3-fluorobenzyl;
-O-P 3 comprising-O-Y, -O-SO 2 CH 3 、-O-SO 2 CF 3 、-OTs、-OBs、-O-CH 2 OCH 3 、-O-C(CH 3 ) 3 、-O-CH 2 Ph、-O-p-methoxybenzyl、-OTMS、-OTES、-OTBDMS、-OTBDPS、-OTIPS、-O-CPh 3 At least one of (a) and (b);
the X comprises at least one of halogen, methoxy and ethoxy; y comprises halogen.
2. The process for preparing a suvorexant intermediate according to claim 1, wherein the first-stage reaction is a substitution reaction catalyzed by a catalyst in a solvent comprising at least one of tetrahydrofuran, acetonitrile, dichloromethane, dimethylformamide, dimethylacetamide, cyclohexane, and n-hexane; when X is at least one of methoxy and ethoxy, the catalyst is an acid catalyst, and the acid catalyst is at least one of acetic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid and citric acid; when X is halogen, the catalyst is an alkaline catalyst, and the alkaline catalyst is at least one of triethylamine, 1,8 diazabicyclo (5.4.0) undec 7 ene, N-diisopropylethylamine, 4-dimethylaminopyridine, N-methylmorpholine, piperidine, pyridine, N-methylpiperazine, sodium bicarbonate, potassium carbonate, sodium hydroxide, cesium carbonate and sodium phosphate; preferably, the solvent is at least one of tetrahydrofuran, dichloromethane and cyclohexane, the acid catalyst is at least one of acetic acid, trifluoroacetic acid and phosphoric acid, and the basic catalyst is at least one of triethylamine, 1,8 diazabicyclo (5.4.0) undec 7 ene, N-diisopropylethylamine and sodium bicarbonate.
3. The process for preparing a suvorexant intermediate according to claim 1, wherein the second-stage reaction is a substitution reaction carried out by reacting a compound of formula II with a reagent a in a solvent under the action of an alkaline reagent, wherein the solvent is at least one of dichloromethane, toluene, xylene, ethyl acetate, isopropyl acetate, acetonitrile, tetrahydrofuran, dimethylformamide, dimethylacetamide, and acetone, the alkaline reagent is at least one of triethylamine, 1,8 diazabicyclo (5.4.0) undec 7 ene, N-diisopropylethylamine, 4-dimethylaminopyridine, N-methylmorpholine, piperidine, pyridine, N-methylpiperazine, sodium bicarbonate, potassium carbonate, sodium hydroxide, cesium carbonate, sodium phosphate, and the reagent a is at least one of phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, p-toluenesulfonyl chloride, methanesulfonyl chloride, and trifluoromethanesulfonyl chloride.
4. The process for the preparation of suvorexant intermediate according to claim 1, wherein the three-stage reaction is an alkylation reaction carried out by reacting a compound of formula III with a compound of formula IV in a solvent which is at least one of dichloromethane, toluene, xylene, ethyl acetate, isopropyl acetate, acetonitrile, tetrahydrofuran, N-dimethylformamide, acetone.
5. The process for preparing a suvorexant intermediate according to claim 1, wherein the four-stage reaction comprises the steps of: the compound of formula V is reacted with a reaction productThe agent B carries out amino protecting group removal reaction in a solvent, the obtained intermediate product is dissolved in an alkaline organic solvent and undergoes condensation reaction, and finally the intermediate product reacts with concentrated hydrochloric acid in a salifying solvent to obtain a compound of a formula VI; the reactant B is hydrochloric acid, trifluoroacetic acid, formic acid, hydrobromic acid, hydrazine and Pd (OH) 2 /C, pd/C and PdCl 2 At least one of/C.
6. A process for the preparation of a suvorexant intermediate according to claim 5, wherein the amino protecting group removal reaction is carried out using a solvent selected from the group consisting of methylene chloride, toluene, xylene, ethyl acetate, isopropyl acetate, acetonitrile, tetrahydrofuran, dimethylformamide, dimethylacetamide, acetone, and C 1 -C 4 At least one of lower alcohols.
7. The process for preparing suvorexant intermediate according to claim 5, wherein said basic organic solvent comprises a base and an organic solvent selected from the group consisting of methylene chloride, toluene, xylene, ethyl acetate, isopropyl acetate, acetonitrile, tetrahydrofuran, dimethylformamide, dimethylacetamide, acetone, and C 1 -C 4 At least one of lower alcohols, wherein the base is at least one of triethylamine, 1,8 diazabicyclo (5.4.0) undec 7 ene, N-diisopropylethylamine, 4-dimethylaminopyridine, N-methylmorpholine, piperidine, pyridine, N-methylpiperazine, sodium bicarbonate, potassium carbonate, sodium hydroxide, cesium carbonate and sodium phosphate.
8. The process for preparing a suvorexant intermediate according to claim 5, wherein said salifying solvent is at least one of dimethylacetamide and toluene, dimethylacetamide and acetone, dimethylacetamide, acetone and water, N-dimethylformamide and toluene, N-dimethylformamide and acetone, N-dimethylformamide, acetone and water.
9. Use of a process for the preparation of a suvorexant intermediate according to any one of claims 1 to 8 for the preparation of suvorexant.
10. A method for preparing su Wo Leisheng, comprising the steps of: the suvorexant intermediate prepared by the preparation method of the suvorexant intermediate of claims 1-8 is subjected to condensation reaction with a compound of formula VII to obtain suvorexant, wherein the compound of formula VII has the following structural formula:
CN202310473883.7A 2023-04-27 2023-04-27 Preparation method and application of Perilla Wo Leisheng intermediate Pending CN116675681A (en)

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