CN110577489B - Synthetic method of narcotic analgesic - Google Patents

Synthetic method of narcotic analgesic Download PDF

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CN110577489B
CN110577489B CN201910876886.9A CN201910876886A CN110577489B CN 110577489 B CN110577489 B CN 110577489B CN 201910876886 A CN201910876886 A CN 201910876886A CN 110577489 B CN110577489 B CN 110577489B
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CN110577489A (en
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李莉娥
郭建锋
曹路
陈雷
周园林
李�杰
杜文涛
汪淼
田峦鸢
吕金良
廖宗权
曲龙妹
李禹琼
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Yichang Humanwell Pharmaceutical Co Ltd
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract

The invention discloses a synthetic method of a narcotic analgesic drug, which takes 4-piperidinecarboxylic acid as a raw material and prepares the narcotic analgesic drug through alkylation, bromination, methylation, acylation and other steps. The method avoids using virulent cyanide, and improves the safety and controllability of operation; the elimination reaction in the reaction process is avoided, the reaction speed is accelerated, the reaction time is shortened, and the method reduces the reaction temperature and shortens the reaction time, and is more suitable for industrial production.

Description

Synthetic method of narcotic analgesic
Technical Field
The invention relates to the technical field of pharmaceutical chemistry, in particular to a synthetic method of an anesthetic analgesic, especially a synthetic method of remifentanil and carfentanil.
Background
Remifentanil is the latest mu opioid receptor agonist, is a novel powerful analgesic, has definite curative effect, strong medicinal effect, quick response, small and easily controlled dose, low toxicity, safety and reliability, and is approved for clinical use in the United states in 1996. Carfentanil (carfenntanil), chemically known as methyl 1- (2-phenylethyl) -4- (N-propionyl-N-phenylamino) -4-piperidinecarboxylate, is an analogue of fentanyl and is a high-intensity and short-acting narcotic analgesic. Their chemical structures are as follows:
Figure RE-GDA0002266594260000011
the current literature for the synthesis of remifentanil and carfentanil is dominated by the following 2 routes:
the synthesis route of carfentanil is reported by Ju, pharmaceutical industry, 1988, 19 (9),
Figure RE-GDA0002266594260000012
chinese patent application CN200680043182.4 reports a synthetic route of remifentanil,
Figure RE-GDA0002266594260000021
according to the synthesis method disclosed by the above document, highly toxic cyanide is used in the synthesis of both remifentanil and carfentanil, and a lot of potential safety hazards exist in the test and production processes; in addition, when piperidine 4-carboxyl methyl esterification is carried out, the reaction time is too long, the reflux is carried out in methanol for more than 90 hours, the reaction of reactants is incomplete, and the conversion rate is only about 70%, so that the yield of the step is extremely low, only about 50%, and the total yield of the whole route is low, only about 10%. The synthesis route is long, the operation is complicated, and the industrial production is not facilitated.
Disclosure of Invention
The following is a summary of the subject matter described in detail herein. This summary is not intended to limit the scope of the claims.
In order to solve the technical problems in the prior art, the invention provides a synthetic method of an anesthetic analgesic drug which is safe to produce, short in reaction route, simple and convenient to operate and easy to industrially produce, wherein the synthetic method comprises remifentanil and carfentanil, and the synthetic method can also be used for preparing intermediate compounds of the remifentanil and the carfentanil, so that the defects in the prior art are overcome.
The invention provides a synthetic method of an anesthetic analgesic, which comprises the following steps:
(1) Reacting the compound of formula (II) with an alkylating agent to obtain a compound of formula (III);
Figure RE-GDA0002266594260000031
(2) Reacting the compound shown in the formula (III) with thionyl chloride and bromine to obtain a compound shown in a formula (IV);
Figure RE-GDA0002266594260000032
(3) Reacting the compound of formula (IV) with activated aniline in methanol to obtain a compound of formula (V);
Figure RE-GDA0002266594260000033
(4) Reacting the compound of formula (V) with a propionating agent to produce a compound of formula (VI);
Figure RE-GDA0002266594260000034
here, the narcotic analgesic is a compound represented by formula (I) or a pharmaceutically acceptable salt thereof:
Figure RE-GDA0002266594260000035
r in the compounds of the formulae (III) to (VI) 1 is-CH 2 -CH 2 -C(O)-O-R 4 、-CH 2 -CH 2 -C(O)-NH 2 、 -CH 2 -CH 2 -C(O)-H、-CH 2 -CH 2 -C.ident.N, or 2-phenylethyl, wherein R 4 Is C1-C4 alkyl or benzyl, selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl or benzyl;
r in the Compounds of formulae (I) to (VI) 2 Is hydrogen or C1-C4 alkyl (preferably methyl);
r in the compound of formula (I) 3 is-CH 2 -CH 2 -C(O)-O-CH 3 Or 2-phenylethyl.
In embodiments herein, the alkylating agent may be a reagent containing a substituted or leaving group, such as a halogenating reagent, or a sulfonate reagent (e.g., a tosylate reagent or a mesylate reagent), more preferably, a halide or sulfonate of the following groups (e.g., tosylate or mesylate): -CH 2 -CH 2 -C(O)-O-R 4 、-CH 2 -CH 2 -C(O)-NH 2 、-CH 2 -CH 2 -C(O)-H、 -CH 2 -CH 2 -C ≡ N, or 2-phenylethyl, wherein R is 4 Is C1-C4 alkyl or benzyl, and can be selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl or benzyl.
In embodiments herein, the alkylating agent may be an electron deficient group containing agent, including but not limited to the following agents:
CH 2 ＝CH-C(O)-O-R 4 、CH 2 ＝CH-C(O)-NH 2 、CH 2 ＝CH-C(O)-H、CH 2 = CH-C ≡ N, or styrene, where R is 4 Is C1-C4 alkyl or benzyl, and can be selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl or benzyl.
In embodiments of the present application, R in the compounds of formulae (III) to (VI) 1 Is not-CH 2 -CH 2 -C(O)-O-CH 3 Or 2-phenylethyl, the synthesis further comprises a functional group transformation reaction such that R in the compounds of formulae (III) to (VI) 1 Conversion to-CH 2 -CH 2 -C(O)-O-CH 3 (ii) a The functional group conversion reaction can be carried out by hydrolyzing esters and amides to carboxylic acids, oxidizing aldehydes to carboxylic acids, and reacting the carboxylic acids with methanol to form methyl esters under catalysis of sulfuric acid or thionyl chloride using methods known in the art. When R in the compound of formula (VI) 1 is-CH 2 -CH 2 -C(O)-O-CH 3 Or 2-phenylethyl, the compound of formula (VI) is the compound of formula (I).
In embodiments of the present application, the method of synthesizing the narcotic analgesic drug optionally further includes reacting the compound of formula (I) with a pharmaceutically acceptable acid to provide a pharmaceutically acceptable acid salt of the compound of formula (I).
In the embodiment of the present application, the compound of formula (II) of step (1) is reacted with an alkylating agent preferably in an organic solvent 1, wherein the organic solvent 1 may be selected from one or a mixture of several of tetrahydrofuran, acetonitrile, acetone, toluene, 2-methyltetrahydrofuran and N, N-dimethylformamide.
In embodiments herein, the activated aniline of step (3) is a compound of formula (VII):
Figure RE-GDA0002266594260000051
r in the formula (VII) 5 Preferred as the electron-withdrawing group is trichloroacetyl, trifluoromethanesulfonyl, p-toluenesulfonyl, or nitrobenzoyl (e.g., 3-nitrobenzoyl). Here, the nitrobenzoyl group means 4-nitrobenzoyl group, 3, 5-dinitrobenzoyl group, 3, 4-dinitrobenzoyl group and the like.
The compound of formula (VII) is unstable in alkaline aqueous solution and can be removed by neutralization with aqueous alkali solution during post-treatment.
In an embodiment herein, the reaction of step (3) is carried out in the presence of a catalyst, which may be trifluoroacetic acid or methanesulfonic acid.
In some embodiments herein, the reaction of step (3) is carried out in a reaction solvent selected from one or more of methanol, acetic acid, acetonitrile and nitromethane.
In some embodiments herein, the temperature of the reaction of step (3) is from-5 ℃ to 30 ℃.
In some embodiments herein, the compound of formula (IV) obtained in step (3) may be used directly in step (4) without isolation.
In some embodiments of the present application, the propionating agent of step (4) is propionic anhydride, or propionyl chloride.
In some embodiments herein, optionally, the reaction of step (4) is performed under a catalyst, the catalyst being one or more of triethylamine, potassium carbonate, sodium bicarbonate, morpholine, and pyridine.
In a preferred embodiment of the present application, the step (1) is: adding a compound of formula (II) and 1-5 equivalents of an alkylating reagent into an organic solvent 1, reacting for 2-20 hours at 30-100 ℃, evaporating the solvent and the residual alkylating reagent under reduced pressure after the reaction is finished, and recrystallizing by using an alcohol solvent (wherein the alcohol solvent is selected from one or more of methanol, ethanol, isopropanol or butanol) to obtain a compound of formula (III).
In a preferred embodiment of the present application, the step (2) is: dissolving 1mol of a compound shown in a formula (III) in an organic solvent 2, controlling the temperature of a reaction system to be 0-10 ℃, dropwise adding 1-2 equivalents of thionyl chloride, controlling the temperature to be about 0 ℃ after the reaction is finished at 20-30 ℃, dropwise adding 1-1.5 equivalents of bromine, heating to reflux, keeping the temperature for reaction for 5 hours, cooling after the reaction is finished, evaporating the solvent under reduced pressure, adding the residue into methanol, and reacting at room temperature to finish to obtain a methanol solution of a compound shown in a formula (IV) for later use; here, the organic solvent 2 is a mixed solvent of one or more of acetonitrile, tetrahydrofuran, acetone, 2-methyltetrahydrofuran, N-dimethylformamide, and toluene.
In a preferred embodiment of the present application, the activated aniline of step (3) can be prepared by the following process:
93.1g (1 mol) of aniline is dissolved in 450ml of organic solvent 3, the internal temperature is controlled to be 0-10 ℃,1 equivalent of anhydride or acyl chloride is dripped, the reaction solution is naturally heated to room temperature until the reaction is finished, and the reaction solution is concentrated to be dry, and the organic solvent 4 is used for reservation. Here, the organic solvent 3 is a mixed solvent of one or more of acetonitrile, tetrahydrofuran, acetone, 2-methyltetrahydrofuran, N-dimethylformamide, and toluene; the organic solvent 4 is a mixed solvent of one or more of methanol, acetic acid, acetonitrile and nitromethane; the acid anhydride is trifluoroacetic anhydride, trichloroacetic anhydride or trifluoromethanesulfonic anhydride, and the acid chloride is nitrobenzoyl chloride (e.g., 3-nitrobenzoyl chloride).
In a preferred embodiment of the present application, the step (3) is: cooling the solution of activated aniline (compound of formula (VII)) to-10-0 ℃, dripping a catalyst, controlling the temperature below 0 ℃, stirring for 1-3 hours, dripping a methanol solution of the compound of formula (IV), controlling the temperature to-5-30 ℃ for reaction, pouring the reaction solution into water after the reaction is finished, extracting by using an organic solvent 5, neutralizing an organic layer by using an aqueous alkali solution, drying a drying agent, filtering, and concentrating the organic layer under reduced pressure to obtain the compound of formula (V). Here, the catalyst is trifluoroacetic acid or methanesulfonic acid; the organic solvent 5 is a mixed solvent of one or more of dichloromethane, ethyl acetate and methyl tert-butyl ether; the alkaline water solution is sodium bicarbonate solution, sodium carbonate solution, potassium carbonate solution or sodium hydroxide solution.
In the synthesis process of the compound of the formula (V), in order to avoid the dehydration elimination reaction of bromine in the compound of the formula (IV) in the reaction process, the lower reaction temperature is controlled in the reaction process, the stirring time of the compound of the formula (IV) is reduced, trifluoroacetic acid or methanesulfonic acid is used as a catalyst, the reaction conditions are controlled by adopting the measures, the unexpected reaction effect is obtained, the elimination reaction of the compound of the formula (IV) in the reaction process is avoided, the reaction speed is accelerated, and the reaction time is shortened to 3-10 hours.
In a preferred embodiment of the present application, the step (4) is: dissolving the compound of formula (V) in an organic solvent 6, adding 0.5-3 equivalents of catalyst, controlling the reaction temperature below 30 ℃, dropwise adding a propionylation reagent, reacting at 20-100 ℃ after dropwise adding, performing HPLC tracking reaction, after 2-15 hours of reaction, pouring the reaction liquid into water, extracting with an organic solvent 7, neutralizing an organic layer with an aqueous alkali solution, drying a drying agent, filtering, and concentrating under reduced pressure by using an organic phase to obtain the compound of formula (VI). Here, the organic solvent 6 is a mixed solvent of one or more of acetonitrile, tetrahydrofuran, acetone, 2-methyltetrahydrofuran, N-dimethylformamide, and toluene; the organic solvent 7 is a mixed solvent of one or more of dichloromethane, ethyl acetate and methyl tert-butyl ether; the catalyst is one or a mixture of more of triethylamine, potassium carbonate, sodium bicarbonate, morpholine and pyridine; the propionylation reagent is as follows: propionic anhydride or propionyl chloride; the alkaline water solution is sodium bicarbonate solution, sodium carbonate solution, potassium carbonate solution or sodium hydroxide solution.
In an embodiment of the present application, the synthesis method optionally further comprises a purification step of formula (I), for example, a method of patent CN201010610912.2, to purify remifentanil, 376.5g of crude remifentanil is dissolved in 2L of methanol, 126g of oxalic acid dihydrate is added, stirring is performed at room temperature to form oxalate, crystallization is performed at 0-5 ℃, filtering is performed, the oxalate of remifentanil is recrystallized by methanol or ethanol, alkali is dissociated, and drying is performed to obtain remifentanil.
The present inventors have carried out remifentanil intermediate compound (V) (R) in documents CN200680043182.4, 1-benzyl-4-methoxycarbonyl-4-anilinopiperidine, pharmaceutical industry, 1987,18 (7), etc 2 Is hydrogen, R 1 is-CH 2 -CH 2 -C(O)-O-CH 3 ) The synthesis of the compound is that when the 4-carboxyl of the piperidine ring of the compound of the formula A is subjected to methyl esterification, the carboxyl is difficult to generate methyl esterification reaction, concentrated sulfuric acid is used as a catalyst, the conversion rate is only about 60 percent after 70-90 hours under the methanol reflux state, and the reaction is continued, so that the raw materials are not converted into products; the thionyl chloride is used as a catalyst, the conversion rate is only about 70 percent, the reaction is continued, and the raw materials are not converted into products. However, when the preparation was carried out by the method of the present invention, no starting material (the compound represented by the formula A in the comparative example) remained in this step from the HPLC chart.
In addition, the synthesis of remifentanil using methyl 4-piperidinecarboxylate as the starting material was found to be difficult to react when α -hydrobromination is carried out in the second reaction step, which may be a reaction mechanism in which the α -hydrogen of the acid chloride is more reactive than the α -hydrogen of the ester.
Compared with the prior art, the synthesis method has at least one of the following advantages:
1. the method has four steps from the initial raw material to the remifentanil preparation, has short reaction route, reduces the synthesis process steps of the remifentanil and the carfentanil, is easy to operate and is more suitable for industrial production.
2. The reagents used in the method are conventional reagents, so that the use of virulent cyanide is avoided, and the safety and controllability of the operation are improved;
3. in the invention, when the compound of the formula (V) is synthesized, in order to avoid the elimination reaction of the compound of the formula (IV) in the reaction process, the traditional alkali catalyst of the reaction is changed, acid is used as the catalyst, the elimination reaction of the compound of the formula (IV) in the reaction process is avoided, the reaction speed is accelerated, and the reaction time is shortened to 3-10 hours.
4. The synthesis of the compound shown in the formula (V) successfully solves the problem that the piperidine ring 4-carboxyl is difficult to methyl-esterify, and the method reduces the reaction temperature, shortens the reaction time and is more suitable for industrial production.
5. Compared with the prior art, the synthesis process can obviously improve the yield and the purity of remifentanil and carfentanil, and is more suitable for industrial production.
Additional features and advantages of the invention will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by the practice of the invention. The objectives and other advantages of the invention will be realized and attained by the structure particularly pointed out in the written description and claims hereof.
Drawings
FIG. 1 is the bookApplication example 1 preparation of a Compound (R) of formula (V) 2 Is hydrogen, R 1 is-CH 2 -CH 2 -C(O)-O-CH 3 ) HPLC profile of (a);
FIG. 2 shows a compound of formula (V) (R) prepared in comparative example of the present application 2 Is hydrogen, R 1 is-CH 2 -CH 2 -C(O)-O-CH 3 ) HPLC profile of (a);
wherein the first peak in HPLC chromatogram is the compound (R) of formula (V) 2 Is hydrogen, R 1 is-CH 2 -CH 2 -C(O)-O-CH 3 ) A chromatographic peak; the second peak in the HPLC profile is the chromatographic peak for the compound of formula A.
Detailed Description
Hereinafter, embodiments of the present invention will be described in detail in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be noted that the embodiments and features of the embodiments in the present application may be arbitrarily combined with each other without conflict.
In an embodiment of the present invention in which, 1 the H-NMR detector is a Bruker Fourier400 nuclear magnetic resonance spectrometer.
A compound of formula V (R) 2 Is hydrogen, R 1 is-CH 2 -CH 2 -C(O)-O-CH 3 ) The HPLC method of (1) is as follows:
and (3) analyzing the column: cyano-bonded silica gel as a packing material (PhenomenexLuna CN column, 4.6 mm. Times.250mm, 5 μm or equivalent performance column)
Mobile phase: with 0.03mol/L potassium dihydrogen phosphate solution (pH adjusted to 3.0 with phosphoric acid) -methanol-acetonitrile (77
Detection wavelength: 220nm
Column temperature: 30 deg.C
Example 1
(1) A compound (R) of the formula (III) 2 Is hydrogen, R 1 is-CH 2 -CH 2 -C(O)-O-CH 3 ) Synthesis of (2)
A compound of formula (II) (R) 2 Hydrogen) compound 129g, dissolved in 800ml acetonitrile, added with methyl acrylate 175g, heated to 85 ℃, refluxed for 5 hours, after the reaction is completed, the reaction solution was concentrated under reduced pressure to remove the solventThe solvent and the remaining methyl acrylate, and the residue was recrystallized from methanol and dried under reduced pressure at 40 ℃ to obtain 195.6g of a white solid, yield: 91 percent.
1 H-NMR(400MHz，CDCl 3 )，δ＝1.59～1.95(m，4H)，2.35～2.57(m， 7H)，3.62(s，3H)，3.76～3.83(m，2H)。
(2) A compound of formula (IV) (R) 2 Is hydrogen, R 1 is-CH 2 -CH 2 -C(O)-O-CH 3 ) Synthesis of (2)
Reacting a compound (R) of formula (III) 2 Is hydrogen, R 1 is-CH 2 -CH 2 -C(O)-O-CH 3 ) 191.7g of the compound is dissolved in 2L 2-methyltetrahydrofuran, the temperature is reduced, the internal temperature is controlled to be 0 to 10 ℃, 107.1g of thionyl chloride is dripped, the reaction is carried out for 3 hours at the temperature of 20 to 30 ℃, the temperature is controlled to be about 0 ℃, 144g of bromine is dripped, the temperature is increased to reflux, the reaction is carried out for 5 hours under the condition of heat preservation, the reaction is finished, the temperature is reduced, the solvent is evaporated under reduced pressure, the residue is added into 405ml of methanol, the reaction is carried out at room temperature until the reaction is finished, and the compound (R) shown in the formula (IV) is obtained 2 Is hydrogen, R 1 is-CH 2 -CH 2 -C(O)-O-CH 3 ) The methanol solution is ready for use.
(3) A compound of formula (VII) (R) 5 Is trifluoroacetyl group) of a compound
Dissolving 83.8g of aniline in 405ml of acetone, controlling the internal temperature to be 0-10 ℃, dropwise adding 189g of trifluoroacetic anhydride, naturally heating to room temperature after the dropwise adding is finished until the reaction is finished, concentrating the reaction solution until the reaction solution is dry, dissolving the reaction solution in 180ml of acetonitrile, and keeping the solution for later use.
(4) A compound of formula (V) (R) 2 Is hydrogen, R 1 is-CH 2 -CH 2 -C(O)-O-CH 3 ) Synthesis of (2)
Reacting the activated aniline (compound of formula (VII), R) obtained in step (3) 5 Is trifluoroacetyl group) is cooled to minus 10 to 0 ℃, 0.01g of trifluoroacetic acid is dripped, the temperature is controlled below 0 ℃ and stirred for 1 to 2 hours, the methanol solution of the compound shown in the formula (IV) obtained in the step (2) is dripped, the temperature is controlled to minus 5 to 10 ℃ for reaction, after the reaction is finished, the reaction solution is poured into water and extracted by dichloromethane, an organic layer is neutralized by sodium bicarbonate aqueous solution, anhydrous magnesium sulfate is dried, filtration is carried out, the organic phase is decompressed and concentrated to be dry, and the compound shown in the formula (V) (R) is obtained 2 Is hydrogen, R 1 is-CH 2 -CH 2 -C(O)-O-CH 3 ) 271.8g, as white solid, yield: 95% and HPLC detection results are shown in FIG. 1.
1 H-NMR(400MHz，CDCl 3 )，δ＝1.90～2.15(m，4H)，2.83～3.06(m， 6H)，3.61(s，3H)，3.67(s，3H)，3.71～3.75(t，2H)，6.63～6.68(m， 1H)，6.81～6.85(m，2H)，7.04～7.09(m，2H)，7.23(s，1H)
(5) A compound of formula (I) (R) 2 Is hydrogen, R 3 is-CH 2 -CH 2 -C(O)-O-CH 3 I.e. remifentanil) synthesis
Reacting a compound (R) of formula (V) 2 Is hydrogen, R 1 is-CH 2 -CH 2 -C(O)-O-CH 3 ) 268.8g is dissolved in 2.7L acetonitrile, 45.5g triethylamine is added, the reaction temperature is controlled below 30 ℃, 78.1g propionyl chloride is dripped, the reaction is carried out at 20-30 ℃ after the dripping is finished, the HPLC tracking reaction is carried out, the reaction liquid is poured into water after the reaction is finished for 10-15 hours, the dichloromethane is used for extraction, the organic layer is neutralized by sodium carbonate aqueous solution, anhydrous sodium sulfate is dried, the filtration is carried out, the organic phase is decompressed and concentrated, and the compound (R) of the formula (VI) is obtained 2 Is hydrogen, R 1 is-CH 2 -CH 2 -C(O)-O-CH 3 ) I.e. compounds of formula (I) (R) 2 Is hydrogen, R 3 is-CH 2 -CH 2 -C(O)-O-CH 3 I.e. remifentanil) 296.8g, yield: 94 percent.
A compound of formula (I) (R) 2 Is hydrogen, R 3 is-CH 2 -CH 2 -C(O)-O-CH 3 I.e., remifentanil) purification process:
293.7g of remifentanil crude product obtained in the step is dissolved in 1.6L of methanol, 98.3g of oxalic acid dihydrate is added, the mixture is stirred at room temperature to form oxalate, crystallization is carried out at the temperature of 0-5 ℃, the filtrate is obtained, the oxalate of remifentanil is recrystallized by methanol, sodium bicarbonate solution is dissociated, and the filtrate is dried under reduced pressure to obtain 265.2g of remifentanil crude product with yield: 90 percent.
Example 2
(1) A compound of formula (III) (R) 2 Is hydrogen, R 1 As 2-phenylethyl) is used
General formula(II) Compound (R) 2 Hydrogen) 129g, dissolving in 800ml tetrahydrofuran, controlling the temperature to be about 0 ℃, dropwise adding beta-phenethyl bromide 185-200g, reacting at 30-40 ℃, concentrating the reaction solution under reduced pressure after the reaction is finished, recrystallizing the residue with isopropanol, drying under reduced pressure at 40 ℃ to obtain 207.3g of white solid, and obtaining the yield: 89 percent.
1 H-NMR(400MHz，CDCl 3 )，δ＝1.56～1.87(m，4H)，2.23～2.55(m， 5H)，2.67～2.71(t，4H)，7.17～7.28(m，5H)，10.62(s，1H)。
(2) A compound of formula (IV) (R) 2 Is hydrogen, R 1 Is 2-phenylethyl)
Reacting a compound (R) of formula (III) 2 Is hydrogen, R 1 Is 2-phenethyl) 198g is dissolved in 2.7L acetone, the temperature is reduced, the internal temperature is controlled to be 0-10 ℃, 101.2g of thionyl chloride is dripped, the reaction is carried out for 3 hours at the temperature of 20-30 ℃, the temperature is controlled to be about 0 ℃, 153g of bromine is dripped, the temperature is increased to reflux, the reaction is kept for 4 hours, the temperature is reduced after the reaction is finished, the solvent is evaporated under reduced pressure, the residue is added into 340ml of methanol, and the reaction is carried out at room temperature until the reaction is finished, thus obtaining the compound (R) of the formula (IV) 2 Is hydrogen, R 1 2-phenylethyl) in methanol for use.
(3) A compound of formula (VII) (R) 5 Is trichloroacetyl group)
79.1g of aniline is dissolved in 385ml of acetonitrile, the internal temperature is controlled to be 0-10 ℃, 262.4g of trichloroacetic anhydride is dripped, the temperature is naturally raised to the room temperature until the reaction is finished, and the reaction solution is concentrated to be dry and is dissolved in 153ml of methanol for standby.
(4) A compound of formula (V) (R) 2 Is hydrogen, R 1 Is 2-phenylethyl)
The activated aniline (compound of formula (VII), R) obtained in step (3) 5 Trichloroacetyl) is cooled to-10 to 0 ℃, 9.6g of methanesulfonic acid is dripped, the temperature is controlled below 0 ℃, the mixture is stirred for 1 to 2 hours, and the compound (R) of the formula (IV) obtained in the step (2) is dripped 2 Is hydrogen, R 1 2-phenethyl), controlling the temperature to be 10-20 ℃ for reaction, pouring the reaction liquid into water after the reaction is finished, extracting the reaction liquid by methyl tert-butyl ether, neutralizing an organic layer by using sodium hydroxide aqueous solution, drying anhydrous sodium sulfate, filtering, and obtaining an organic phaseConcentrating under reduced pressure to dryness to obtain compound (R) of formula (V) 2 Is hydrogen, R 1 2-phenylethyl) 250.6g as a white solid, yield: 91 percent.
1 H-NMR(400MHz，CDCl 3 )，δ＝1.71～2.13(m，4H)，2.43～2.56(m， 4H)，2.66～3.68(t，4H)，6.67(m，1H)，6.71～6.75(m，2H)，7.03～7.28 (m，8H)，12.23(s，1H)
(5) A compound of formula (I) (R) 2 Is hydrogen, R 3 Is 2-phenylethyl, i.e. carfentanil) synthesis
Reacting a compound (R) of formula (V) 2 Is hydrogen, R 1 2-phenylethyl) 226.8g is dissolved in 2.1L acetone, 96.6g of anhydrous potassium carbonate is added, the reaction temperature is controlled to be below 25 ℃, 119g of propionic anhydride is dropwise added, the reaction is carried out at 50-60 ℃, HPLC tracking reaction is carried out for 5-7 hours, the reaction liquid is poured into water and extracted by ethyl acetate, the organic layer is neutralized by potassium carbonate aqueous solution, anhydrous sodium sulfate is dried, the filtration is carried out, the organic phase is decompressed and concentrated to obtain the compound (R) of the formula (VI) 2 Is hydrogen, R 1 Is 2-phenylethyl), i.e. a compound of formula (I) (R) 2 Is hydrogen, R 3 254g for crude 2-phenylethyl, i.e. carfentanil), yield: 92 percent.
A compound of formula (I) (R) 2 Is hydrogen, R 3 2-phenylethyl, i.e. carfentanil):
dissolving 248.5g of carfentanil crude product obtained in the step in 1.3L of ethanol, adding 79.4g of oxalic acid dihydrate, stirring at room temperature to form oxalate, crystallizing at 0-5 ℃, filtering, recrystallizing the oxalate of carfentanil with methanol, dissociating sodium carbonate solution, drying under reduced pressure to obtain 224.3g of yield: and 90 percent.
Example 3
(1) A compound (R) of the formula (III) 2 Is hydrogen, R 1 is-CH 2 -CH 2 -C(O)-NH 2 ) Synthesis of (2)
Reacting a compound (R) of formula (II) 2 Hydrogen) 129g, dissolving in 800ml of acetone, adding 108g of acrylamide, heating to 50-60 ℃, refluxing for 7 hours, concentrating the reaction solution under reduced pressure after the reaction is finished, removing the solvent and the residual acrylamide, and using methyl acetate as the residuePulping and purifying the tert-butyl ether, and drying the product at 40 ℃ under reduced pressure to obtain 173g of white solid, wherein the yield is as follows: 86 percent.
1 H-NMR(400MHz，DMSO-d 6 )，δ＝1.63～1.92(m，4H)，2.33～2.59(m， 7H)，3.62～3.65(d，2H)，7.53(s，2H)，12.45(s，1H)。
(2) A compound of formula (IV) (R) 2 Is hydrogen, R 1 is-CH 2 -CH 2 -C(O)-NH 2 ) Synthesis of (2)
Reacting a compound (R) of formula (III) 2 Is hydrogen, R 1 is-CH 2 -CH 2 -C(O)-NH 2 ) 170g of the compound (R) is dissolved in 1.7L of acetonitrile, the temperature is reduced, the internal temperature is controlled to be 0-10 ℃, 101.2g of thionyl chloride is dripped, the reaction is carried out for 2 hours at the temperature of 45-60 ℃, the temperature is controlled to be about 0 ℃, 136g of bromine is dripped, the temperature is raised to reflux, the reaction is carried out for 5 hours under the condition of heat preservation, the reaction is finished, the temperature is reduced, the solvent is evaporated under reduced pressure, the residue is added into 385ml of methanol, and the reaction is carried out at the room temperature until the reaction is finished, thus obtaining the compound (R) of the formula (IV) 2 Is hydrogen, R 1 is-CH 2 -CH 2 -C(O)-NH 2 ) The methanol solution is ready for use.
(3) A compound of formula (VII) (R) 5 Is trifluoromethanesulfonyl) synthesis
79.1g of aniline is dissolved in 385ml of tetrahydrofuran, the internal temperature is controlled to be 0-5 ℃, 240g of trifluoromethanesulfonic anhydride is dripped, the temperature is naturally raised to room temperature after the dripping is finished, the reaction solution is concentrated to be dry and is dissolved by 153ml of acetic acid, and the solution is reserved for use.
(4) A compound of formula (V) (R) 2 Is hydrogen, R 1 is-CH 2 -CH 2 -C(O)-NH 2 ) Synthesis of (2)
Activating the aniline (compound of formula (VII), R) obtained in step (3) 5 Trifluoromethanesulfonyl) acetic acid solution is cooled to-5 to 0 ℃, 0.1g of trifluoroacetic acid is dripped, the temperature is controlled below 0 ℃, the mixture is stirred for 1 to 2 hours, and the compound (R) of the formula (IV) obtained in the step (2) is dripped 2 Is hydrogen, R 1 is-CH 2 -CH 2 -C(O)-NH 2 ) Controlling the temperature of the methanol solution to be 20-30 ℃ for reaction, pouring the reaction solution into water after the reaction is finished, extracting the reaction solution by using ethyl acetate, neutralizing an organic layer by using a potassium carbonate aqueous solution, drying the organic layer by using anhydrous magnesium sulfate, filtering the dried organic layer and the organic layerConcentrating the organic phase under reduced pressure to dryness to obtain the compound (R) of the formula (V) 2 Is hydrogen, R 1 is-CH 2 -CH 2 -C(O)-NH 2 ) 230.7g, as white solid, yield: 89 percent.
1 H-NMR(400MHz，CDCl 3 )，δ＝1.87～2.05(m，4H)，2.43～2.56(m， 6H)，3.61～3.69(m，5H)，6.63～6.68(m，1H)，6.81～6.87(m，2H)， 7.03～7.07(m，4H)，7.25(s，1H)
Reacting a compound (R) of formula (V) 2 Is hydrogen, R 1 is-CH 2 -CH 2 -C(O)-NH 2 ) Heating in hydrochloric acid solution 60 for hydrolysis, and catalyzing the obtained product with sulfuric acid or thionyl chloride in methanol to obtain a compound (R) of formula (V) 2 Is hydrogen, R 1 is-CH 2 -CH 2 -C(O)-O-CH 3 ) The product of (1).
(5) A compound of formula (I) (R) 2 Is hydrogen, R 3 is-CH 2 -CH 2 -C(O)-O-CH 3 I.e. remifentanil) synthesis
The compound (R) of the formula (V) prepared above 2 Is hydrogen, R 1 is-CH 2 -CH 2 -C(O)-O-CH 3 ) 224g of the compound is dissolved in 2.2L 2-methyltetrahydrofuran, 55.4g of pyridine is added, the reaction temperature is controlled to be below 30 ℃, 119g of propionic anhydride is dripped, the reaction is carried out at 50-60 ℃ after the dripping is finished, the HPLC tracking reaction is carried out, the reaction solution is poured into water after the reaction is finished for 10-15 hours, dichloromethane is used for extraction, the organic layer is neutralized by sodium bicarbonate aqueous solution, anhydrous sodium sulfate is dried, the filtration is carried out, the organic phase is subjected to pressure concentration, and the compound (R) with the formula (VI) is obtained 2 Is hydrogen, R 1 is-CH 2 -CH 2 -C(O)-O-CH 3 ) I.e. a compound (R) of formula (I) 2 Is hydrogen, R 3 is-CH 2 -CH 2 -C(O)-O-CH 3 I.e., remifentanil) crude 240.5g, yield: 91.3 percent.
A compound of formula (I) (R) 2 Is hydrogen, R 3 is-CH 2 -CH 2 -C(O)-O-CH 3 I.e., remifentanil) purification process:
237.2g of remifentanil crude product prepared above is dissolved in 1.26L of methanol, 79.4g of oxalic acid dihydrate is added, the mixture is stirred at room temperature to be oxalate, crystallization is carried out at 0-5 ℃, the filtrate is obtained, the oxalate of remifentanil is recrystallized by methanol, sodium bicarbonate solution is dissociated, and reduced pressure drying is carried out to obtain 214.2g of the remifentanil crude product, wherein the yield is as follows: 90 percent.
Example 4
(1) A compound of formula (III) (R) 2 Is hydrogen, R 1 is-CH 2 -CH 2 -C ≡ N) synthesis
Reacting a compound (R) of formula (II) 2 Hydrogen) 129g, dissolving in 800ml of 2-methyltetrahydrofuran, adding 60g of acrylonitrile, heating to 70-80 ℃, refluxing for reaction for 3 hours, concentrating the reaction solution under reduced pressure after the reaction is finished, removing the solvent and the residual acrylonitrile, pulping and purifying the residue with isopropyl ether, and drying under reduced pressure at 40 ℃ to obtain 169.2g of white solid, wherein the yield is as follows: 93 percent.
1 H-NMR(400MHz，CDCl 3 )，δ＝1.60～1.86(m，4H)，2.34～2.57(m， 5H)，2.62～2.75(t，2H)，3.04～3.12(t，2H)，10.47(s，1H)。
(2) A compound of formula (IV) (R) 2 Is hydrogen, R 1 is-CH 2 -CH 2 -C.ident.N) synthesis
Reacting a compound (R) of formula (III) 2 Is hydrogen, R 1 is-CH 2 -CH 2 -C.ident.N) 163.8g is dissolved in 1.8L toluene, the temperature is reduced, the inner temperature is controlled to be 0-10 ℃, 107.1g of thionyl chloride is dripped, the reaction is carried out for 1h at 70-80 ℃, the temperature is controlled to be about 0 ℃, 144g of bromine is dripped, the temperature is raised to 80 ℃, the reaction is carried out for 3 hours under heat preservation, the temperature is reduced after the reaction is finished, the solvent is evaporated under reduced pressure, the residue is added into 405ml of methanol, and the reaction is carried out at 45 ℃ until the completion, thus obtaining the compound (R) of the formula (IV) 2 Is hydrogen, R 1 is-CH 2 -CH 2 -C ≡ N) in methanol for use.
(3) A compound of formula (VII) (R) 5 Is 3-nitrobenzoyl) group
Dissolving 83.8g of aniline in 450ml of 2-methyltetrahydrofuran, controlling the internal temperature to be minus 5-0 ℃, dropwise adding 167g of 3-nitrobenzoyl chloride, naturally heating to room temperature after the dropwise adding is finished until the reaction is finished, concentrating the reaction liquid until the reaction liquid is dried, dissolving 162ml of nitromethane and keeping the mixture for later use.
(4) A compound of formula (V) (R) 2 Is hydrogen, R 1 is-CH 2 -CH 2 -C.ident.N) synthesis
Reacting the activated aniline (compound of formula (VII), R) obtained in step (3) 5 Cooling a nitromethane solution of 3-nitrobenzoyl) to-5-0 ℃, dropwise adding 6.8g of methanesulfonic acid, controlling the temperature to be below 0 ℃, stirring for 1-2 hours, dropwise adding a methanol solution of the compound shown in the formula (IV) obtained in the step (2), controlling the temperature to be-5-10 ℃ for reaction, pouring a reaction solution into water after the reaction is finished, extracting by using ethyl acetate, neutralizing an organic layer by using a sodium bicarbonate aqueous solution, drying by anhydrous magnesium sulfate, filtering, and concentrating the organic layer to be dry under reduced pressure to obtain the compound shown in the formula (V) (R) 2 Is hydrogen, R 1 is-CH 2 -CH 2 -C ≡ N) 232.5g as white solid, yield: 90 percent.
1 H-NMR(400MHz，CDCl 3 )，δ＝1.89～2.03(m，4H)，2.41～2.53(m， 4H)，3.68～3.73(t，2H)，3.03～3.11(t，2H)，3.71(s，3H)，6.63～6.67 (m，1H)，6.81～6.89(m，2H)，7.09～7.14(m，2H)，7.27(s，1H)
Subjecting the compound (R) of the formula (V) obtained above to 2 Is hydrogen, R 1 is-CH 2 -CH 2 -C.ident.N) in hydrochloric acid solution at 60 deg.C, and catalyzing the obtained product with sulfuric acid or thionyl chloride in methanol to obtain compound (R) of formula (V) 2 Is hydrogen, R 1 is-CH 2 -CH 2 -C(O)-CH 3 ) The product of (1).
(5) A compound of formula (I) (R) 2 Is hydrogen, R 3 is-CH 2 -CH 2 -C(O)-CH 3 I.e. remifentanil) synthesis
Reacting a compound (R) of formula (V) 2 Is hydrogen, R 1 is-CH 2 -CH 2 -C(O)-CH 3 ) 229.6g is dissolved in 2.5L tetrahydrofuran, 85.6g morpholine is added, the reaction temperature is controlled below 30 ℃, 136g propionic anhydride is dripped, the reaction is carried out at 45-60 ℃ after finishing dripping, HPLC tracking reaction is carried out, the reaction liquid is poured into water after 10-15 hours of reaction, dichloromethane is used for extraction, the organic layer is neutralized by sodium bicarbonate aqueous solution, anhydrous sodium sulfate is dried, filtration is carried out, the organic phase is decompressed and concentrated, and the compound (R) of the formula (VI) is obtained 2 Is hydrogen, R 1 is-CH 2 -CH 2 -C(O)-O-CH 3 ) I.e. compounds of formula (I) (R) 2 Is hydrogen, R 3 is-CH 2 -CH 2 -C(O)-CH 3 I.e. remifentanil) crude 279.6g, yield: and 93 percent.
A compound of formula (I) (R) 2 Is hydrogen, R 3 is-CH 2 -CH 2 -C(O)-CH 3 I.e., remifentanil) purification process:
dissolving 274.8g of remifentanil crude product obtained in the above step in 1.56L of methanol, adding 92g of oxalic acid dihydrate, stirring at room temperature to form oxalate, crystallizing at 0-5 ℃, filtering, recrystallizing the remifentanil oxalate with methanol, dissociating sodium bicarbonate solution, and drying under reduced pressure to obtain 248.2g of the product with yield: 90 percent.
Example 5
(1) A compound (R) of the formula (III) 2 Is hydrogen, R 1 Is 2-phenylethyl)
Reacting a compound (R) of formula (II) 2 Hydrogen) 129g, dissolving in 1000ml of N, N-dimethylformamide, adding 160g of styrene, reacting at 110-120 ℃, concentrating the reaction liquid under reduced pressure after the reaction is finished, recrystallizing the residue by ethanol, drying under reduced pressure at 40 ℃ to obtain 205g of white solid, and obtaining the yield: 88 percent.
1 H-NMR(400MHz，CDCl 3 )，δ＝1.56～1.87(m，4H)，2.23～2.55(m， 5H)，2.67～2.71(t，4H)，7.17～7.28(m，5H)，10.62(s，1H)。
(2) A compound of formula (IV) (R) 2 Is hydrogen, R 1 Is 2-phenylethyl)
Reacting a compound (R) of formula (III) 2 Is hydrogen, R 1 Is 2-phenethyl) 198g is dissolved in 1.7L toluene, the temperature is reduced, the internal temperature is controlled to be 0-10 ℃, 102g of thionyl chloride is dripped in the mixture, the mixture reacts for 3 hours at the temperature of 20-30 ℃, the temperature is controlled to be about 0 ℃, 153g of bromine is dripped in the mixture, the mixture is heated to reflux, the mixture reacts for 4 hours under heat preservation, the temperature is reduced, the solvent is evaporated under reduced pressure after the reaction is finished, the residue is added into 400ml of methanol, and the reaction is finished at room temperature, thus obtaining the compound (R) of the formula (IV) 2 Is hydrogen, R 1 2-phenylethyl) in methanol for use.
(3) A compound of formula (VII) (R) 5 Is p-toluenesulfonylBase) synthesis
79.1g of aniline is dissolved in 382ml of toluene, the internal temperature is controlled to be 0-10 ℃, 161.5g of p-methyl benzene sulfonyl chloride is added in batches, the temperature is raised to 60 ℃ until the reaction is finished, and the reaction solution is concentrated to be dry and dissolved in 153ml of acetic acid for standby.
(4) A compound of the formula (V) (R) 2 Is hydrogen, R 1 As 2-phenylethyl) is used
Reacting the activated aniline (compound of formula (VII), R) obtained in step (3) 5 P-toluenesulfonyl) acetic acid solution is cooled to-5 to 5 ℃, 0.8g of trifluoromethanesulfonic acid is dripped, the temperature is controlled to be below 0 to 5 ℃, the mixture is stirred for 1 to 2 hours, and the compound (R) of the formula (IV) obtained in the step (2) is dripped 2 Is hydrogen, R 1 2-phenethyl), controlling the temperature to be 10-20 ℃ for reaction, pouring the reaction liquid into water after the reaction is finished, extracting by methyl tert-butyl ether, neutralizing an organic layer by using sodium hydroxide aqueous solution, drying by using anhydrous sodium sulfate, filtering, concentrating the organic phase under reduced pressure to be dry to obtain a compound (R) shown in the formula (V) 2 Is hydrogen, R 1 2-phenylethyl) 250.6g as a white solid, yield: 91 percent.
1 H-NMR(400MHz，CDCl 3 )，δ＝1.71～2.13(m，4H)，2.43～2.56(m， 4H)，2.66～3.68(t，4H)，6.67(m，1H)，6.71～6.75(m，2H)，7.03～7.28 (m，8H)，12.23(s，1H)
(5) A compound of formula (I) (R) 2 Is hydrogen, R 3 Is 2-phenylethyl, i.e. carfentanil) synthesis
Reacting a compound (R) of formula (V) 2 Is hydrogen, R 1 2-phenylethyl) 243g is dissolved in 2.25L N, N-dimethylformamide, 90g of anhydrous sodium bicarbonate is added, the reaction temperature is controlled below 25 ℃, 127.5g of propionic anhydride is dropwise added, the reaction is carried out at 80-100 ℃, HPLC tracking reaction is carried out for 5-7 hours, the reaction liquid is poured into water, ethyl acetate is used for extraction, the organic layer is neutralized by potassium carbonate aqueous solution, anhydrous sodium sulfate is dried, filtration is carried out, organic phase is subjected to pressure concentration, and the compound (R) of the formula (VI) is obtained 2 Is hydrogen, R 1 Is 2-phenylethyl), i.e. a compound of formula (I) (R) 2 Is hydrogen, R 3 269.2g crude 2-phenylethyl, i.e., carfentanil), yield: 90.9 percent.
A compound of formula (I) (R) 2 Is hydrogen, R 3 2-phenylethyl, i.e. carfentanil) process:
dissolving 256.4g of crude carfentanil in 1.3L of ethanol, adding 81.9g of oxalic acid dihydrate, stirring at room temperature to form oxalate, crystallizing at 0-5 ℃, filtering, recrystallizing the oxalate of carfentanil with methanol, dissociating a sodium carbonate solution, and drying under reduced pressure to obtain 231.4g of the product with yield: 90 percent.
Comparative examples
A compound of formula (V) (R) 2 Is hydrogen, R 1 is-CH 2 -CH 2 -C(O)-O-CH 3 ) Synthesis of (2)
Reference 1-benzyl-4-methoxycarbonyl-4-anilinopiperidine preparation-pharmaceutical industry, 1987,18 (7) the preparation of the Compound of formula (V) (R) 2 Is hydrogen, R 1 is-CH 2 -CH 2 -C(O)-O-CH 3 ) Synthesis of (2)
The synthetic route is as follows:
Figure RE-GDA0002266594260000171
30.6g of the compound of the formula A and 54ml of anhydrous methanol were placed in a 250ml three-necked flask. Slowly dripping 10ml of catalyst concentrated sulfuric acid (or thionyl chloride) under stirring, and stirring and refluxing for 70-90h after dripping. The methanol was evaporated off, the residue was added to ice water and basified to pH =11 with ammonia water at around 0 ℃, and extracted with dichloromethane. The extract was washed with dilute ammonia water and water in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated off. The residue was triturated with isopropyl ether to solidify it, which was filtered to give a white-like solid, i.e., the compound of formula (V) (R) 2 Is hydrogen, R 1 is-CH 2 -CH 2 -C(O)-O-CH 3 ) 15.3g, yield: 41.2 percent, and the purity of the compound shown in the formula V shown in figure 2 is only 64 percent according to HPLC detection results.
Although the embodiments disclosed in the present application are described above, the descriptions are only for the convenience of understanding the present application, and are not intended to limit the present application. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the disclosure as defined by the appended claims.

Claims (9)

1. A synthetic method of an anesthetic analgesic drug comprises the following steps:
(1) Reacting the compound of formula (II) with an alkylating agent to obtain a compound of formula (III);
Figure FDA0003938766790000011
(2) Reacting the compound shown in the formula (III) with thionyl chloride and bromine to obtain a compound shown in a formula (IV);
Figure FDA0003938766790000012
(3) Reacting the compound of formula (IV) with activated aniline in methanol to obtain a compound of formula (V);
Figure FDA0003938766790000013
(4) Reacting the compound of formula (V) with a propionating agent to produce a compound of formula (VI);
Figure FDA0003938766790000014
here, the narcotic analgesic is a compound represented by formula (I) or a pharmaceutically acceptable salt thereof:
Figure FDA0003938766790000021
r in the compounds of the formulae (III) to (VI) 1 is-CH 2 -CH 2 -C(O)-O-R 4 、-CH 2 -CH 2 -C(O)-NH 2 、-CH 2 -CH 2 -C(O)-H、-CH 2 -CH 2 -C.ident.N, or 2-phenylethyl, wherein R 4 Is C1-C4 alkyl or benzyl;
r in the Compounds of formulae (I) to (VI) 2 Is hydrogen or C1-C4 alkyl;
r in the compound of formula (I) 3 is-CH 2 -CH 2 -C(O)-O-CH 3 Or 2-phenylethyl;
the activated aniline of step (3) is a compound of formula (VII):
Figure FDA0003938766790000022
r in the formula (VII) 5 Is trichloroacetyl, trifluoromethanesulfonyl, p-toluenesulfonyl, or nitrobenzoyl;
and, the reaction of the step (3) is carried out in the presence of a catalyst, the catalyst being trifluoroacetic acid or methanesulfonic acid.
2. The synthetic method according to claim 1, wherein the alkylating agent of step (1) is a halide or sulfonate of: -CH 2 -CH 2 -C(O)-O-R 4 、-CH 2 -CH 2 -C(O)-NH 2 、-CH 2 -CH 2 -C(O)-H、-CH 2 -CH 2 -C.ident.N, or 2-phenylethyl, wherein R 4 Is C1-C4 alkyl or benzyl;
alternatively, the alkylating agent is the following:
CH 2 ＝CH-C(O)-O-R 4 、CH 2 ＝CH-C(O)-NH 2 、CH 2 ＝CH-C(O)-H、CH 2 ＝CH-C
either [ identical to ] N or styrene, wherein R 4 Is C1-C4 alkyl or benzyl.
3. The method of synthesis of claim 2, wherein theThe alkylating agent of step (1) is a halide or sulfonate of the following groups: -CH 2 -CH 2 -C(O)-O-R 4 、-CH 2 -CH 2 -C(O)-NH 2 、-CH 2 -CH 2 -C(O)-H、-CH 2 -CH 2 -C.ident.N, or 2-phenylethyl, wherein R 4 Is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl or benzyl;
alternatively, the alkylating agent is the following:
CH 2 ＝CH-C(O)-O-R 4 、CH 2 ＝CH-C(O)-NH 2 、CH 2 ＝CH-C(O)-H、CH 2 ＝CH-C
n, or styrene, wherein R is 4 Is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl or benzyl.
4. The process of claim 1 wherein R is in the compounds of formulae (III) to (VI) 1 Is not-CH 2 -CH 2 -C(O)-O-CH 3 Or 2-phenylethyl, the synthesis further comprises a functional group transformation reaction such that R in the compounds of formulae (III) to (VI) 1 Conversion to-CH 2 -CH 2 -C(O)-O-CH 3 ；
When R in the compound of formula (VI) 1 is-CH 2 -CH 2 -C(O)-O-CH 3 Or 2-phenylethyl, the compound of formula (VI) is the compound of formula (I).
5. The synthesis method according to claim 1, wherein the compound of formula (II) in step (1) is reacted with an alkylating agent in an organic solvent 1, wherein the organic solvent 1 is one or more selected from tetrahydrofuran, acetonitrile, acetone, toluene, 2-methyltetrahydrofuran and N, N-dimethylformamide.
6. The synthesis method according to any one of claims 1 to 5, wherein the reaction of step (3) is carried out in a reaction solvent selected from one or more of methanol, acetic acid, acetonitrile and nitromethane; or
The reaction temperature in the step (3) is-5 ℃ to 30 ℃; or
The compound of formula (IV) obtained in step (3) is used directly in step (4) without isolation.
7. The synthesis according to any one of claims 1 to 5, wherein the propionating agent of step (4) is propionic anhydride, or propionyl chloride; or
The reaction in the step (4) is carried out under the presence of a catalyst, wherein the catalyst is one or more of triethylamine, potassium carbonate, sodium bicarbonate, morpholine and pyridine.
8. The synthesis method according to any one of claims 1 to 5, wherein the step (1) is: adding a compound of a formula (II) and 1-5 equivalents of an alkylating reagent into an organic solvent 1, reacting for 2-20 hours at 30-100 ℃, decompressing, evaporating and removing the solvent and the residual alkylating reagent, and recrystallizing by using an alcohol solvent to obtain a compound of a formula (III).
9. The synthesis method according to any one of claims 1 to 5, wherein the step (2) is: dissolving 1mol of a compound shown in a formula (III) in an organic solvent 2, controlling the temperature of a reaction system to be 0-10 ℃, dropwise adding 1-2 equivalents of thionyl chloride, controlling the temperature to be 0 ℃ after the reaction is finished at 20-30 ℃, dropwise adding 1-1.5 equivalents of bromine, heating to reflux, carrying out heat preservation reaction for 5 hours, cooling after the reaction is finished, evaporating the solvent under reduced pressure, adding the residue into methanol, and reacting at room temperature to finish to obtain a methanol solution of a compound shown in a formula (IV) for later use; here, the organic solvent 2 is a mixed solvent of one or more of acetonitrile, tetrahydrofuran, acetone, 2-methyltetrahydrofuran, N-dimethylformamide, and toluene; or
The step (3) is as follows: cooling the activated aniline solution to-10-0 ℃, dropwise adding a catalyst, controlling the temperature below 0 ℃, stirring for 1-3 hours, dropwise adding a methanol solution of the compound shown in the formula (IV), controlling the temperature to-5-30 ℃ for reaction, pouring a reaction solution into water after the reaction is finished, extracting by using an organic solvent 5, neutralizing an organic layer by using an aqueous alkali solution, drying a drying agent, filtering, and concentrating the organic phase under reduced pressure to obtain a compound shown in the formula (V); here, the catalyst is trifluoroacetic acid or methanesulfonic acid; the organic solvent 5 is a mixed solvent of one or more of dichloromethane, ethyl acetate and methyl tert-butyl ether; the alkaline water solution is sodium bicarbonate solution, sodium carbonate solution, potassium carbonate solution and sodium hydroxide solution; or alternatively
The step (4) is as follows: dissolving the compound shown in the formula (V) in an organic solvent 6, adding 0.5-3 equivalents of a catalyst, controlling the reaction temperature below 30 ℃, dropwise adding a propionating agent, reacting at 20-100 ℃ after dropwise adding, performing HPLC tracking reaction, after 2-15 hours of reaction, pouring the reaction liquid into water, extracting by using an organic solvent 7, neutralizing an organic layer by using an aqueous alkali solution, drying a drying agent, filtering, and concentrating under reduced pressure by using an organic phase to obtain the compound shown in the formula (VI); here, the organic solvent 6 is a mixed solvent of one or more of acetonitrile, tetrahydrofuran, acetone, 2-methyltetrahydrofuran, N-dimethylformamide, and toluene; the organic solvent 7 is a mixed solvent of one or more of dichloromethane, ethyl acetate and methyl tert-butyl ether; the catalyst is one or a mixture of more of triethylamine, potassium carbonate, sodium bicarbonate, morpholine and pyridine; the propionylation reagent is as follows: propionic anhydride or propionyl chloride; the alkaline water solution is sodium bicarbonate solution, sodium carbonate solution, potassium carbonate solution or sodium hydroxide solution.
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