CN116143652A - Alfosa intermediate and preparation method and application thereof - Google Patents

Alfosa intermediate and preparation method and application thereof Download PDF

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CN116143652A
CN116143652A CN202310199887.0A CN202310199887A CN116143652A CN 116143652 A CN116143652 A CN 116143652A CN 202310199887 A CN202310199887 A CN 202310199887A CN 116143652 A CN116143652 A CN 116143652A
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glycine
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CN116143652B (en
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李豪
李友强
李�杰
邵波
王颖
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Sichuan Qingmu Pharmaceutical Co ltd
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    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/70Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/84Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
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    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00Preparation of carboxylic acid amides
    • C07C231/02Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D261/00Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/04Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
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    • Y02P20/55Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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Abstract

The invention belongs to the field of pharmaceutical chemistry, and particularly discloses an aforana intermediate and a preparation method thereof, and application of the intermediate in preparation of aforana medicaments, and the invention has the following beneficial effects: the synthesis raw materials are cheap and easy to obtain, the intermediate preparation condition is mild, the operation is safe, the environmental pollution is small, and the method is more suitable for industrialized mass production.

Description

Alfosa intermediate and preparation method and application thereof
Technical Field
The invention relates to the field of pharmaceutical chemistry, in particular to an aforana intermediate, a preparation method thereof and application of the intermediate in preparation of aforana medicines.
Background
The new-generation oral in vitro insect repellent Nishi (NexGard) (common name: affrana chewing tablet) for dogs is the first oral insect repellent for dogs for killing two parasites, namely ticks and fleas. The Nishi belongs to the isoxazoline family, and is a revolutionary powerful pesticide by inhibiting GABA chloride ion channels to make arthropod nerves highly excited to death. Wherein the chemical name is 4- [5- [ 3-chloro-5- (trifluoromethyl) phenyl ] -4, 5-dihydro-5- (trifluoromethyl) -3-isoxazolyl ] -nitrogen- [ 2-oxo-2- [ (2, 2-trifluoroethyl) amino ] ethyl ] -1-naphthacenecarboxamide, and the structural formula is as follows:
Figure BDA0004108804630000011
patent WO2009002809A2 discloses a method for preparing aforana, which has a long preparation route, a low yield and difficulty in purification due to the use of an insertion reaction in the presence of a catalyst in the final butt joint step, and fragments 1, 2 and 3 are not produced in a large amount in industry, and all require customization or self synthesis. Therefore, it is necessary to develop a new, more suitable, industrialized, lower cost method for preparing aforana.
Figure BDA0004108804630000012
Disclosure of Invention
In order to solve the problems of long preparation route, low yield and high cost of the Alfosa reaction in the prior art, the invention provides an Alfosa intermediate and a preparation method thereof.
The invention provides an intermediate, which has a structure shown in a formula (1)
Figure BDA0004108804630000021
R 1 Selected from H or C 1 -C 6 An alkyl group;
R 1 preferably H or C 1 -C 3 An alkyl group.
In some specific embodiments, the intermediate is selected from the following compounds:
Figure BDA0004108804630000022
the invention also provides a preparation method of the intermediate, which comprises the following steps:
reacting the compound of the formula a with glycine ester derivatives to prepare an intermediate of the formula (1);
Figure BDA0004108804630000023
wherein R is 1 As defined above.
Further, the reaction of the compound of the formula a and the glycine ester derivative also comprises the activation by using a condensing agent, wherein the condensing agent is selected from CDI, DCC or EDCI; the temperature of activation with the condensing agent is 0-85 ℃, preferably 0-45 ℃, most preferably 15-25 ℃.
Further, the reaction of the compound of the formula a and the glycine ester derivative also comprises methane sulfonic acid, and the molar ratio of the methane sulfonic acid to the compound of the formula a is 2:1; the molar ratio of condensing agent to compound of formula a is (1-2): 1, preferably (1.2-1.6): 1; the molar ratio of the glycine ester derivative to the compound of formula a is (1-2): 1, preferably (1.2-1.6): 1.
Further, the glycine ester derivative is selected from glycine ethyl ester hydrochloride, glycine isopropyl ester hydrochloride or glycine benzyl ester hydrochloride; preferably glycine ethyl ester hydrochloride.
Further, the reaction solvent of the compound of the formula a and the glycine ester derivative is selected from halogenated alkanes, esters, ethers, sulfoxides or nitriles; preferably, the esters are selected from ethyl acetate, isopropyl acetate or butyl acetate; the ethers are selected from diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran or 1,4 dioxane; the halogenated alkane is selected from chloromethane or dichloromethane; the sulfoxide is selected from dimethyl sulfoxide, diethyl sulfoxide or benzyl sulfoxide; the nitriles are selected from acetonitrile or propionitrile; more preferably, the reaction solvent of the compound of formula a and glycine ester derivative is selected from dichloromethane, ethyl acetate, tetrahydrofuran, dimethyl sulfoxide or acetonitrile.
Further, the reaction temperature of the compound of formula a and the glycine ester derivative is 0 to 85 ℃, preferably 20 to 80 ℃, more preferably 60 to 80 ℃, and even more preferably 70 to 80 ℃.
Further, the reaction time of the compound of formula a and the glycine ester derivative is 1-48h, preferably 1-24h.
The invention also provides a method for preparing aforana by using the intermediate, which comprises the following steps:
Figure BDA0004108804630000031
step 1: reacting the intermediate of the formula (1) with triethylamine hydrochloride to obtain an intermediate d;
step 2: intermediate d is reacted with 1- (3-chloro-5- (trifluoromethyl) phenyl) -2, 2-trifluoroethan-1-one to afford intermediate e;
step 3: intermediate e reacts with hydroxylamine derivatives to obtain aforana.
Further, the condensing agent is selected from CDI, DCC or EDCI in the step 1.
Further, the molar ratio of the triethylamine hydrochloride to the intermediate of the formula (1) in the step 1 is (1-2): 1, preferably (1-1.4): 1.
Further, the reaction temperature in the step 1 is-10 to 20 ℃, preferably-10 to 10 ℃, more preferably-5 to 5 ℃.
Further, the reaction solvent of step 1 is selected from esters, ethers or haloalkanes as defined above, preferably the reaction solvent of step 1 is selected from dichloromethane, isopropyl acetate, acetonitrile or toluene.
Further, the reaction time of the step 1 is 1 to 48 hours, preferably 1 to 20 hours.
Further, the step 2 also comprises a base, wherein the base is selected from K 2 HPO 4 ·3H 2 O、K 3 PO 4 、Na 2 HPO 4 ·12H 2 O、Na 3 PO 4 Or CH (CH) 3 COONa, preferably Na 3 PO 4 The method comprises the steps of carrying out a first treatment on the surface of the The molar ratio of the base to the intermediate d is (0.1-2): 1, preferably (0.1-1.4): 1.
Further, the reaction solvent of step 2 is selected from the group consisting of amides, esters, aromatic hydrocarbons or nitriles, selected from the group consisting of formamide, N-dimethylacetamide, N-dimethylformamide, N-methylpyrrolidone, N-dimethyl-2-imidazolidinone or hexamethylphosphoramide, the esters, aromatic hydrocarbons or nitriles being as defined above, preferably, the reaction solvent of step 2 is selected from the group consisting of N, N-dimethylformamide, isopropyl acetate, acetonitrile or toluene.
Further, the molar ratio of 2, 2-trifluoro-1- [ 3-chloro-5- (trifluoromethyl) phenyl ] ethanone to intermediate d in step 2 is (1-2): 1, preferably (1-1.4): 1.
Further, the reaction temperature of the step 2 is 90 ℃ or reflux reaction.
Further, the reaction time of the step 2 is 1 to 48 hours, preferably 3 to 27 hours.
Further, the step 3 also comprises a base, wherein the base is selected from NaOH and C 2 H 5 ONa、DBU、Na 2 CO 3 TEA or KOH, preferably DBU, naOH or KOH; the molar ratio of base to intermediate e is (2-4): 1, preferably (2.5-3.5): 1.
Further, the reaction solvent of step 3 is selected from ethers selected from diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran or 1,4 dioxane, preferably tetrahydrofuran or 2-methyltetrahydrofuran.
Further, the hydroxylamine derivative in the step 3 is selected from hydroxylamine hydrochloride or hydroxylamine sulfate, preferably hydroxylamine hydrochloride, and the molar ratio of the hydroxylamine derivative to the intermediate e is (0.1-2): 1, preferably (0.5-1.4): 1.
Further, the reaction temperature of the step 3 is 0 to 80 ℃, preferably 5 to 60 ℃.
Further, the reaction time of the step 3 is 1 to 24 hours, preferably 3 to 21 hours.
In some specific embodiments, the method of preparing aforana further comprises the steps of: reacting the compound of the formula a with glycine ester derivatives to prepare an intermediate of the formula (1);
when R is 1 When the compound is not H, the compound of the formula a is mixed with glycinateThe derivative reaction also comprises strong alkali, wherein the strong alkali is selected from NaOH, KOH or LiOH; the molar ratio of the strong base to the compound of formula a is (1-2): 1, preferably (1-1.5): 1;
Figure BDA0004108804630000041
further, the reaction of the compound of the formula a and the glycine ester derivative also comprises the activation by using a condensing agent, wherein the condensing agent is selected from CDI, DCC or EDCI; the temperature of activation with the condensing agent is 0-85 ℃, preferably 0-45 ℃, most preferably 15-25 ℃.
Further, the reaction of the compound of the formula a and the glycine ester derivative also comprises methane sulfonic acid, and the molar ratio of the methane sulfonic acid to the compound of the formula a is 2:1; the molar ratio of condensing agent to compound of formula a is (1-2): 1, preferably (1.2-1.6): 1; the molar ratio of the glycine ester derivative to the compound of formula a is (1-2): 1, preferably (1.2-1.6): 1.
Further, the glycine ester derivative is selected from glycine ethyl ester hydrochloride, glycine isopropyl ester hydrochloride or glycine benzyl ester hydrochloride; preferably glycine ethyl ester hydrochloride.
Further, the reaction solvent of the compound of the formula a and the glycine ester derivative is selected from halogenated alkanes, esters, ethers, sulfoxides or nitriles; preferably, the esters are selected from ethyl acetate, isopropyl acetate or butyl acetate; the ethers are selected from diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran or 1,4 dioxane; the haloalkane is selected from dichloromethane; the sulfoxide is selected from dimethyl sulfoxide, diethyl sulfoxide or benzyl sulfoxide; the nitriles are selected from acetonitrile or propionitrile; more preferably, the reaction solvent of the compound of formula a and glycine ester derivative is selected from dichloromethane, ethyl acetate, tetrahydrofuran, dimethyl sulfoxide or acetonitrile.
Further, the reaction temperature of the compound of formula a and the glycine ester derivative is 0 to 85 ℃, preferably 20 to 80 ℃, more preferably 60 to 80 ℃, and even more preferably 70 to 80 ℃.
Further, the reaction time of the compound of formula a and the glycine ester derivative is 1-48h, preferably 1-24h.
In some specific embodiments, the method of preparing aforana comprises the steps of:
step 1: reacting a compound of the formula a with glycine ethyl ester hydrochloride under the action of methane sulfonic acid and CDI to obtain an intermediate b;
step 2: reacting the intermediate b with NaOH to obtain an intermediate c;
step 3: reacting the intermediate c with triethylamine hydrochloride under the action of CDI to obtain an intermediate d;
step 4: intermediate d and 1- (3-chloro-5- (trifluoromethyl) phenyl) -2, 2-trifluoroethan-1-one in Na 3 PO 4 The reaction is carried out under the action of the catalyst to obtain an intermediate e;
step 5: intermediate e reacts with hydroxylamine hydrochloride under the action of NaOH to obtain the aforana.
Figure BDA0004108804630000061
The invention has the following beneficial effects:
(1) Compared with the prior art, the invention has the advantages that the reaction cost is obviously reduced, the 2-amino-N- (2, 2-trifluoroethyl) acetamide which is high in price (17250 yuan/kg) and difficult to self-prepare and purify is not required to be used as a material, the glycine ethyl ester hydrochloride (78-86.5 yuan/kg) and the trifluoroethylamine hydrochloride (1000-1500 yuan/kg) are used as materials, the cost is reduced to 10 percent of the prior art, the yield of the obtained aforana is higher than that of the prior art, the production cost is greatly reduced, and the method is more suitable for industrialized mass production.
(2) The experiment that the preparation condition of the intermediate is mild and the reaction batch is increased to the kilogram level proves that the invention overcomes the problem of incomplete raw material reaction caused by equipment amplification (amplification effect) by specifically adding methane sulfonic acid as a reaction reagent, has higher yield and purity of the intermediate, and is more suitable for industrial mass production.
Detailed Description
The present invention is described in further detail below with reference to examples, but is not limited to the following examples, and any equivalents in the art, which are in accordance with the present disclosure, are intended to fall within the scope of the present invention.
The structure of the compound is characterized by Mass Spectrum (MS) or nuclear magnetic resonance 1 HNMR).
Nuclear magnetic resonance 1 HNMR) displacement (δ) is given in parts per million (ppm); nuclear magnetic resonance 1 HNMR) was measured using a bruker avance-400 nuclear magnetic instrument with deuterated dimethyl sulfoxide (DMSO) as the measuring solvent and Tetramethylsilane (TMS) as the internal standard.
The Mass Spectrum (MS) measuring instrument is Agilent LCMS 1200-6110.
In the case where no specific explanation is given to the present invention, the solution mentioned in the reaction of the present invention is an aqueous solution.
The term "room temperature" according to the invention means a temperature between 15℃and 35 ℃.
The term "amplification effect" according to the present invention refers to the results of studies carried out by chemical process experiments using small-sized equipment, which tend to differ greatly from the results obtained by large-sized production units under the same operating conditions, the effect of these differences being referred to as amplification effect.
The abbreviations for the reactants used in the examples of the present invention are explained in the following table:
Figure BDA0004108804630000071
example 1 preparation of intermediate b
Figure BDA0004108804630000072
Taking 1000mL of a three-necked flask, sequentially adding 800mL of acetonitrile and 100.0g of a under stirring, controlling the temperature within T to be 20+/-5 ℃, adding 106.0g of N, N' -carbonyldiimidazole in batches, obviously releasing heat, releasing a large amount of gas, carrying out heat preservation reaction for 1h, then controlling the temperature within 20+/-5 ℃ to drop 89.7g of methanesulfonic acid, and carrying out heat preservation stirring for 0.5h after the completion of the drop. 91.3g of glycine ethyl ester hydrochloride are then added in portions, the heat is obviously released, the temperature is raised to 75+/-5 ℃, the temperature is kept and stirred for 1h, and the standard is controlled in the middle: a is less than or equal to 3.0 percent. Cooling to the temperature of less than or equal to 60 ℃ in T, concentrating under reduced pressure until no obvious fraction exists, adding 400mL of dichloromethane and 300mL of water at room temperature, stirring for 0.5h, separating liquid, extracting aqueous phase by 200mL of CM, combining organic phases, washing sequentially by sodium chloride aqueous solution (25 g of sodium chloride+200 mL of water) and sodium bicarbonate aqueous solution (10 g of sodium bicarbonate+200 mL of water), separating liquid, concentrating the organic phase under reduced pressure at 50 ℃ to obtain 158.0g of brown-black oily substance, namely an intermediate b, directly adding the intermediate b into the next reaction step according to the yield of 100%, and carrying out the chromatographic purity of 97.50%. The resulting oil was detected by nuclear magnetic resonance and mass spectrometry.
1 H-NMR(400MHz,DMSO-d6):δ9.14-9.11ppm(1H),8.56-8.54ppm(1H),8.32-8.29ppm(1H),8.13ppm(1H),7.69-7.62ppm(3H),4.20ppm(2H),4.10-4.07ppm(2H),2.75ppm(3H),1.27ppm(3H)。
EIMS m/z 300.2([M+H] + )。
The preparation method in example 1 was subjected to screening for the kind and amount of the solvent, the activation temperature and reaction temperature, the reaction time, and the amount of glycine ethyl ester hydrochloride (labeled a in the following table), and the screening results are shown in table 1:
TABLE 1 screening of reaction conditions for the preparation method of example 1
Figure BDA0004108804630000081
Note that: the "V" in the table represents the volume to mass ratio (mL/g) of the reaction solvent to compound a, e.g. DCM 8V means 1g of compound a, 8mL of DCM being added; the designation "eq" represents the molar ratio of reactant/material to compound a, e.g. CDI is used in an amount of 1.4eq, and means that the molar ratio of CDI to compound a is 1.4:1.
the reaction batch in example 1 was increased to kilogram level, a remarkable amplification effect was exhibited, the residue of the compound a was remarkably increased, and the addition of N, N' -Carbonyldiimidazole (CDI) and glycine ethyl ester hydrochloride had no remarkable effect, so that the type and amount of the solvent, the reaction temperature and the type of the acid were further screened, and the results are shown in Table 2.
TABLE 2 screening of reaction conditions in example 1 (kilogram scale reaction)
Figure BDA0004108804630000091
Note that: in the table, where "V" is the volume to mass ratio (mL/g) of the reaction solvent to compound a, for example DCM 4V means 1g of intermediate b, 4mL of DCM is added; the designation "eq" represents the molar ratio of reactant/material to compound a, e.g. CDI is used in an amount of 1.4eq, and means that the molar ratio of CDI to compound a is 1.4:1.
as shown in Table 2, when methanesulfonic acid is added, the purity of the intermediate b is greatly improved, the reaction rate is also obviously improved, and the addition of reagents of formic acid, glacial acetic acid and the like is ineffective, which indicates that methanesulfonic acid can obviously overcome the amplification effect brought by the amplification of reaction equipment, accelerate the reaction, lead the reaction of the raw material compound a to be complete, and obtain unexpected technical effects.
Example 2 preparation of intermediate c
Figure BDA0004108804630000092
Taking 1000ml single-mouth bottle, sequentially adding crude product of intermediate b and 400ml tetrahydrofuran, heating to T Inner part =50±5 ℃, and stirred until the solid is dissolved. The system is cooled to 15-35 ℃, sodium hydroxide aqueous solution (24.3 g sodium hydroxide and 100ml water) prepared in advance is added dropwise, the temperature is obviously raised, the reaction is carried out for 1h at room temperature after the dripping is finished, the HPLC monitoring and the center control standard are adopted: b is less than or equal to 1.0 percent.
130ml of diluted hydrochloric acid (6M/L) was added to the reaction mixture, the pH of the system was adjusted to 2 to 3, and the mixture was concentrated under reduced pressure at 50℃to remove most of tetrahydrofuran, whereby a large amount of solids was precipitated.
300ml of acetonitrile was added to the concentrate, and the temperature was raised to T Inner part =75±5 ℃, stirring at a constant temperature for 30min until the system is dissolved, and dripping 100mL of water. Heating is closed after heat preservation and stirring for 30min, naturally cooling to room temperature, and then ice bath is carried outCooling to T Inner part =5±5 ℃, stirring for 1h with heat preservation, filtering, leaching the filter cake with 100mL, drying under reduced pressure at 60 ℃ for 30h, and collecting 102.0g of light brown solid, the yield is 80.3%, and the chromatographic purity is 99.48%. The obtained solid is detected by nuclear magnetic resonance and mass spectrum.
1 H-NMR(400MHz,DMSO-d6)δ12.75ppm(1H),9.03ppm(1H),8.57-8.54ppm(1H),8.34-8.32ppm(1H),8.13ppm(1H),7.69-7.61ppm(3H),4.03ppm(2H),2.75ppm(3H)。
EIMS m/z 272.4([M+H] + )。
The amount of sodium hydroxide, the reaction temperature and the reaction time were selected in example 2, and the results are shown in Table 3.
TABLE 3 screening of reaction conditions in example 2
Figure BDA0004108804630000101
Note that: the designation "eq" represents the molar ratio of reactant/material to compound a, for example 1.3eq for sodium hydroxide, and means a molar ratio of sodium hydroxide to compound a of 1.4:1.
as shown in Table 3, the purity of the intermediate c was higher (higher than 90%) under different conditions of sodium hydroxide usage, reaction temperature and reaction time, indicating that the above-mentioned changes in reaction conditions had no significant effect on the preparation of intermediate c.
Example 3 preparation of intermediate d
Figure BDA0004108804630000102
Taking 1000mL three-necked flask, sequentially adding 190mL N, N-dimethylformamide and 95.0g of intermediate c under stirring, and cooling to T in an ice bath Inner part =5±5 ℃. 79.5g of N, N' -carbonyldiimidazole are added in portions, and the temperature T is controlled Inner part No significant exotherm was observed, but significant gas evolution was observed, =5±5℃. After the addition is finished, keep T Inner part =5±5 ℃ for 3h. Then 57.0g of trifluoroethylamine hydrochloride is added in batches, the temperature is obviously raised, and the temperature T is controlled Inner part =5±5 ℃. After the addition is finished, keep T Inner part =5±5 ℃ for 3h, center control standard: c is less than or equal to 4.0 percent.
Naturally heating the reaction system to T Inner part Adding aqueous potassium carbonate solution (9.5 g of potassium carbonate+380 mL of water) into the reaction solution, precipitating a large amount of yellow solid, stirring for 1h at a temperature of 20 ℃ C., cooling to T in an ice bath Inner part Keep temperature and stir for 1h =5±5℃. Filtration (difficult filtration) and the filter cake was rinsed with 50mL of water to give M3 wet product.
190mL of acetonitrile is added into the crude product, and the temperature is raised to T Inner part The reaction system was stirred at 75±5 ℃ for 1 hour with heat preservation, and the solid was not dissolved in the reaction system. An aqueous potassium carbonate solution (4.75 g of potassium carbonate+190 mL of water) was added dropwise to the reaction system at a constant temperature, and the solid in the system remained undissolved after the addition. Closing heating, naturally cooling to room temperature, and cooling to T in ice bath Inner part =5±5 ℃, and stirred for 1h with heat preservation. Filtering, leaching the filter cake with 95mL of water, and vacuum drying at 60 ℃ for 48h, and obtaining 109.0g of the obtained product with the yield of 88.6% and the chromatographic purity of 99.35%, namely the intermediate d. The obtained solid is detected by nuclear magnetic resonance and mass spectrum.
1 H-NMR(400MHz,DMSO-d6):δ8.95(1H),8.72ppm(1H),8.56-8.53ppm(1H),8.37-8.34ppm(1H),8.12ppm(1H),7.70-7.61ppm(3H),4.05-3.99ppm(4H),2.75ppm(3H)。
EIMS m/z 353.3([M+H] + )。
The amount of sodium hydroxide, the reaction temperature, the reaction time and the amount of trifluoroethylamine hydrochloride (labeled B in the following table) used in example 3 were selected, and the results of the selection are shown in Table 4.
TABLE 4 screening of reaction conditions in example 3
Figure BDA0004108804630000111
Figure BDA0004108804630000121
Note that: in the table, the "V" is the volume to mass ratio (mL/g) of the reaction solvent to intermediate c, for example DMF 5V, representing 1g of intermediate c, 5mL of DMF being added; the designation "eq" represents the molar ratio of reactant/material to intermediate c, e.g. CDI is used in an amount of 1.4eq, and means that the molar ratio of CDI to intermediate c is 1.4:1.
as shown in Table 4, the purity of the intermediate d was higher under the conditions of different amounts of sodium hydroxide, reaction temperature, reaction time and amount of triethylamine hydrochloride, which indicated that the above-mentioned changes in reaction conditions had no significant effect on the preparation of the intermediate c.
Example 4 preparation of intermediate e
Figure BDA0004108804630000122
1000mL of a three-necked flask was taken, and a thermometer, a water separator and a nitrogen gas protector were added thereto, followed by sequentially adding 400mL of acetonitrile, 100g of d, 94.2g of 2, 2-trifluoro-1- [ 3-chloro-5- (trifluoromethyl) phenyl group]After three times of substitution of ethyl ketone and 28g of sodium phosphate and nitrogen, the temperature is raised to T Inner part Reflux reaction for 21h at 80-83 ℃, system cooling to 50 ℃, concentrating and removing most acetonitrile.
600ml of methyl tert-butyl ether and 200ml of water were added to the concentrate for extraction, the mixture was allowed to stand for demixing, the aqueous phase was extracted with 100ml of methyl tert-butyl ether, the organic phases were combined and washed with 100ml of water. The organic phase was concentrated under reduced pressure at 50 ℃ to give a tan solid. 200ml of acetonitrile was added to the concentrate, and the temperature was raised to T Inner part Dissolving at 75+/-5 ℃, dropwise adding 100ml of water at the temperature, and stirring for 0.5h after the dripping is finished. Closing heating, naturally cooling to room temperature, and cooling to T in ice bath Inner part =5±5 ℃, and stirred for 1h with heat preservation. The filter cake was filtered and rinsed with 50ml of x 3 water. Vacuum drying at 60deg.C for 19h, collecting 143.0g pale yellow solid, namely intermediate e, with a yield of 82.7% and a chromatographic purity of 94.12%. The obtained solid is detected by nuclear magnetic resonance and mass spectrum.
1 H-NMR(400MHz,DMSO-d6):δ8.90ppm(1H),8.73ppm(1H),8.40-8.37ppm(1H),8.35-8.31ppm(1H),8.18ppm(1H),7.915、7.912ppm(1H),7.82ppm(1H),7.72ppm(1H),7.68-7.60ppm(4H),4.05-3.96ppm(4H)。
EIMS m/z 610.9([M+H] + )。
The type and equivalent of the base, the reaction solvent, the amount of 2, 2-trifluoro-1- [ 3-chloro-5- (trifluoromethyl) phenyl ] ethanone (labeled C in the table) and the reaction time in example 4 were selected, and the results are shown in Table 5.
TABLE 5 screening of reaction conditions in example 4
Figure BDA0004108804630000131
Note that: in the table, the "V" is the volume to mass ratio (mL/g) of the reaction solvent to intermediate d, for example, DMF 4V indicates that 1g of intermediate d is to be added with 4mL of DMF; the designation "eq" represents the molar ratio of reactant/material to intermediate d, for example 1.4eq for the amount of base, and means a molar ratio of base to intermediate d of 1.4:1.
as shown in Table 5, the choice of solvent and base in this step has a certain effect on the purity of intermediate e, where Na 3 PO 4 When acetonitrile is used as a solvent, the purity of the intermediate e is the highest, and the intermediate e is the most preferable.
EXAMPLE 5 preparation of Alfosan
Figure BDA0004108804630000141
A2000 ml three-necked flask was taken, 390ml of tetrahydrofuran and 130.0g of intermediate e were sequentially added thereto, and the mixture was dissolved by stirring at room temperature. Cooling in ice bath to T Inner part Slowly adding hydroxylamine hydrochloride aqueous solution (20.7 g hydroxylamine hydrochloride+260 ml water) at a temperature of =5+ -5deg.C, heating to a temperature of significantly controlled temperature T Inner part =5±5 ℃. Slowly dropwise adding sodium hydroxide aqueous solution (23.8 g sodium hydroxide+130 ml water) after the addition, obviously heating, and controlling the temperature T Inner part =5±5 ℃. After the addition was completed, the reaction was stirred for 3 hours and monitored by HPLC.
6N diluted hydrochloric acid (90 ml) was slowly added to the reaction mixture, the pH was 1-3 after the addition, and then 520ml MTBE was added for extraction, and the mixture was allowed to stand for delamination. The aqueous phase was extracted with 260ml of MTBE and the organic phases were combined and washed with 260ml of water (significant emulsification) with the addition of partially saturated sodium chlorideAnd sodium chloride solids, there was still slight emulsification after stirring for 10 min. The separated organic phase was concentrated under reduced pressure to remove most of the solvent, 260ml of methanol was added to the concentrate, and concentrated again under reduced pressure to remove most of the solvent. 585ml of methanol is added into the concentrated solution, and the temperature is raised to T Inner part The concentrate was dissolved in the system at 45-50 ℃, and 195ml of water was added dropwise at constant temperature. After the dripping is finished, the system is slightly turbid, but no obvious solid is separated out, and the temperature is kept for stirring for 1h. Closing heating, changing mechanical stirring, naturally cooling to T Inner part Keep warm and stir overnight =20-25 ℃. Then continue to cool down to T Inner part The mixture was stirred at 5.+ -. 5 ℃ for 1h, filtered and the filter cake rinsed with 260ml water. The filter cake was dried in vacuo at 60℃for 16h to yield 119g of off-white solid. The dried sample is dissolved in 585ml of methanol again and heated to T Inner part The concentrate was dissolved in the system at 45-50 ℃, and 195ml of water was added dropwise at constant temperature. After the dripping is finished, the system is slightly turbid, but no obvious solid is separated out, and the temperature is kept for stirring for 1h. Closing heating, changing mechanical stirring, naturally cooling to T Inner part Keep warm and stir overnight =20-25 ℃. Then continue to cool down to T Inner part The mixture was stirred at 5.+ -. 5 ℃ for 1h, filtered and the filter cake rinsed with 260ml water. The filter cake was dried in vacuo at 60℃for 16h, yielding 110g of off-white solid in 82.6% yield. Taking 1000ml single-mouth bottle, sequentially adding 110g crude product (P0-20210701 batch) and 660ml acetonitrile, heating to T Inner part Keep temperature and stir until system is clear, =45±5℃. And (3) dropwise adding 220ml of water at the temperature, closing heating after the dropwise adding, changing the stirring mode from magnetic stirring to mechanical stirring, and slowly cooling for 19h. Continuing ice bath cooling to T Inner part The mixture was stirred at 5.+ -. 5 ℃ for 1h, filtered and the filter cake rinsed with 220ml water. The filter cake is dried under reduced pressure at 45 ℃ and is recovered to obtain 103.2g of off-white solid, namely the Affordna A crystal form, the yield is 93.8%, and the chromatographic purity is 99.97%. The obtained solid is detected by nuclear magnetic resonance and mass spectrum.
1 H-NMR(400MHz,DMSO-d6):δ8.97-8.95ppm(1H),8.77-8.72ppm(2H),8.41-8.40ppm(1H),8.10-8.06ppm(2H),7.96-7.84ppm(2H),7.76-7.73ppm(3H),4.65-4.60ppm(2H),4.05-3.99ppm(4H)。
EIMS m/z 625.18([M+H] + )。
The conditions of hydroxylamine type, amount, reaction temperature, alkali type, solvent type, reaction time and the like in example 5 were selected, and the results are shown in Table 6.
TABLE 6 screening of reaction conditions for example 5
Figure BDA0004108804630000151
Note that: in the table, the "V" is the volume to mass ratio (mL/g) of the reaction solvent to intermediate e, for example THF 3V, 1g intermediate e, 3mL THF being added; the designation "eq" represents the molar ratio of reactant/material to intermediate e, for example 1.4eq for the amount of base, and means a molar ratio of base to intermediate e of 1.4:1.
as shown in Table 6, the selection of hydroxylamine type and base in this step has a certain influence on the purity of aforana, and among them, when hydroxylamine hydrochloride is selected as the hydroxylamine type, the highest purity of aforana is the most preferable, with alkali such as NaOH, KOH or DBU as the base.
Although the invention has been described herein with reference to illustrative embodiments thereof, it should be understood that numerous other modifications and embodiments can be devised by those skilled in the art that will fall within the scope and spirit of the principles of this disclosure. More specifically, various variations and modifications may be made to the component parts and/or arrangements of the subject combination arrangement within the scope of the disclosure. In addition to variations and modifications in the component parts and/or arrangements, other uses will be apparent to those skilled in the art.

Claims (10)

1. An intermediate having a structure represented by formula (1):
Figure FDA0004108804620000011
wherein R is 1 Selected from H or C 1 -C 6 An alkyl group;
R 1 preferablyH or C 1 -C 3 An alkyl group.
2. A process for the preparation of an intermediate as claimed in claim 1, comprising the steps of: reacting the compound of the formula a with glycine ester derivatives to prepare an intermediate of the formula (1);
Figure FDA0004108804620000012
wherein R is 1 As defined in claim 1.
3. The preparation method of the aforana is characterized by comprising the following steps of:
Figure FDA0004108804620000013
step 1: reacting the intermediate of the formula (1) with triethylamine hydrochloride to obtain an intermediate d;
step 2: intermediate d is reacted with 1- (3-chloro-5- (trifluoromethyl) phenyl) -2, 2-trifluoroethan-1-one to afford intermediate e;
step 3: reacting the intermediate e with hydroxylamine derivatives to obtain aforana;
wherein R is 1 As defined in claim 1.
4. A method of preparing as claimed in claim 3, further comprising the steps of: reacting the compound of the formula a with glycine ester derivatives to prepare an intermediate of the formula (1);
when R is 1 When the alkali is not H, the reaction of the compound of the formula a and the glycine ester derivative also comprises strong alkali, wherein the strong alkali is selected from NaOH, KOH or LiOH;
Figure FDA0004108804620000021
wherein R is 1 As defined in claim 1.
5. The method of claim 3, wherein step 1 further comprises a condensing agent selected from CDI, DCC, and EDCI; the hydroxylamine derivative in the step 3 is selected from hydroxylamine hydrochloride or hydroxylamine sulfate.
6. The process according to claim 3, wherein the step 2 further comprises a base selected from the group consisting of K 2 HPO 4 ·3H 2 O、K 3 PO 4 、Na 2 HPO 4 ·12H 2 O、Na 3 PO 4 Or CH (CH) 3 COONa。
7. The process according to claim 2 or 4, wherein the reaction of the compound of formula a with glycine ester derivative further comprises methanesulfonic acid.
8. The process according to claim 2 or 4, wherein the solvent for the reaction of the compound of formula a with glycine ester derivatives is selected from esters, ethers, haloalkanes, aromatic hydrocarbons, sulfoxides or nitriles.
9. The method of claim 8, wherein the esters are selected from ethyl acetate, isopropyl acetate, or butyl acetate; the ethers are selected from diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran or 1,4 dioxane; the halogenated alkane is selected from chloromethane or dichloromethane; the aromatic hydrocarbon is selected from benzene, toluene, xylene or chlorobenzene; the sulfoxide is selected from dimethyl sulfoxide, diethyl sulfoxide or benzyl sulfoxide; the nitriles are selected from acetonitrile or propionitrile.
10. The method of manufacturing as claimed in claim 4, comprising the steps of:
step 1: reacting a compound of the formula a with glycine ethyl ester hydrochloride under the action of methane sulfonic acid and CDI to obtain an intermediate b;
step 2: reacting the intermediate b with NaOH to obtain an intermediate c;
step 3: reacting the intermediate c with triethylamine hydrochloride under the action of CDI to obtain an intermediate d;
step 4: intermediate d and 1- (3-chloro-5- (trifluoromethyl) phenyl) -2, 2-trifluoroethan-1-one in Na 3 PO 4 The reaction is carried out under the action of the catalyst to obtain an intermediate e;
step 5: reacting the intermediate e with hydroxylamine hydrochloride under the action of NaOH to obtain aforana;
Figure FDA0004108804620000031
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3150575A1 (en) * 2010-09-27 2017-04-05 E. I. du Pont de Nemours and Company Method for preparing 2-amino-n-(2,2,2-trifluoroethyl) acetamide
CN109195955A (en) * 2016-04-06 2019-01-11 梅里亚股份有限公司 The method of the crystallization toluene solvate for isoxazoline compound-(the S)-afoxolaner being enriched with being used to prepare enantiomerism
JP2020023442A (en) * 2016-12-19 2020-02-13 住友化学株式会社 Oxadiazole compound and plant disease control method
CN115433140A (en) * 2022-11-08 2022-12-06 世华合创生物技术开发(山东)有限公司 Synthetic method of Aforana
CN116253658A (en) * 2022-11-25 2023-06-13 济南久隆医药科技有限公司 Synthesis method of aforana intermediate

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3150575A1 (en) * 2010-09-27 2017-04-05 E. I. du Pont de Nemours and Company Method for preparing 2-amino-n-(2,2,2-trifluoroethyl) acetamide
CN109195955A (en) * 2016-04-06 2019-01-11 梅里亚股份有限公司 The method of the crystallization toluene solvate for isoxazoline compound-(the S)-afoxolaner being enriched with being used to prepare enantiomerism
JP2020023442A (en) * 2016-12-19 2020-02-13 住友化学株式会社 Oxadiazole compound and plant disease control method
CN115433140A (en) * 2022-11-08 2022-12-06 世华合创生物技术开发(山东)有限公司 Synthetic method of Aforana
CN116253658A (en) * 2022-11-25 2023-06-13 济南久隆医药科技有限公司 Synthesis method of aforana intermediate

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