CN107434780B - Preparation method of AR-13324 - Google Patents
Preparation method of AR-13324 Download PDFInfo
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- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
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- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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 relates to a preparation method of AR-13324, the invention utilizes chiral ligand chiral induction to synthesize AR-13324, compared with the existing chiral HP L C method or SFC method, the AR-13324 prepared by adopting the chemical synthesis method has the characteristics of simple operation, simple synthesis condition, low cost, chiral monomer obtained with high purity and high yield.
Description
Technical Field
The invention relates to the field of medicines, in particular to a ROCK kinase and norepinephrine transporter inhibitor, and more particularly relates to a preparation method of an AR-13324 inhibitor.
Background
The AR-13324 is ROCK kinase and norepinephrine transporter inhibitor, the prior method is usually prepared by a chiral HP L C method or an SFC method, the HP L C method is a common method at present, but the cost of a chiral stationary phase is too high, chiral mobile phase additives complicate chromatographic conditions, and the preparation of the AR-13324 by the SFC (supercritical fluid chromatography) has the same problems of high cost and low yield.
Disclosure of Invention
The invention aims to provide a preparation method of AR-13324, which is simple to operate and low in cost.
The specific technical scheme of the invention is as follows:
a preparation method of AR-13324 utilizes chiral ligand chiral induction to synthesize AR-13324, the structural formula of the chiral ligand is shown as formula 5:
The preferred chiral ligand is synthesized by the following steps:
(1) protecting hydroxyl in 4- (hydroxymethyl) phenylacetic acid by TBSCl or TIPSCl to obtain a crude compound 4;
(2) dissolving the compound 4 and the asymmetric synthesis chiral auxiliary agent in an organic solvent, adding oxalyl chloride, cooling with dry ice acetone, and reacting under the action of a catalyst to obtain a chiral ligand, wherein the structural formula of the chiral ligand is shown as formula 5:
The preferable chiral induction synthesis of AR-13324 by using chiral ligand comprises the following steps:
(1) protecting hydroxyl in 4- (hydroxymethyl) phenylacetic acid by TBSCl or TIPSCl to obtain a crude compound 4;
(2) dissolving the compound 4 and the asymmetric synthesis chiral auxiliary agent in an organic solvent, adding oxalyl chloride, cooling with dry ice acetone, and reacting under the action of a catalyst to obtain a chiral ligand, wherein the structural formula of the chiral ligand is shown as formula 5:
(3) dissolving the compound 5, sodium hexamethyldisilazide and the compound 13 in an organic solvent, cooling with dry ice acetone, stirring for reaction, then heating to room temperature, stirring overnight to obtain a crude compound 6, and purifying by passing through a column to obtain a pure compound 6;
(4) adding the compound 6 into an organic solvent and water, cooling with ice water, adding lithium hydroxide, stirring for reaction, adjusting the pH value, evaporating the organic solvent under reduced pressure, filtering, extracting the filtrate, drying, and evaporating to dryness under reduced pressure to obtain a compound 7;
(5) Adding the compound 7, 1-hydroxybenzotriazole and triethylamine into dry dichloromethane, carrying out nitrogen protection, cooling, adding EDCI into a reaction solution, heating and stirring, then carrying out reduced pressure evaporation on the reaction solution until no solvent exists, adding ice water into a residue, adjusting pH, extracting and purifying to obtain a compound 7A;
(6) Adding the compound 7A, 6-aminoisoquinoline and EDCI into pyridine, performing nitrogen protection, then adding 4-dimethylaminopyridine, reacting overnight, and performing reduced pressure evaporation to obtain a compound 8 after complete reaction;
(7) dissolving the compound 8 in an organic solvent, adding hydrazine hydrate into the organic solvent, heating the mixture to reflux, cooling the mixture after the reaction is finished, and filtering the mixture to obtain a compound 9;
(8) introducing tert-butyloxycarbonyl to protect amino in the compound 9 to obtain a compound 10;
(9) adding the compound 10 into an organic solvent, then adding tetrabutyl ammonium fluoride for reaction, and after the reaction is finished, decompressing and evaporating to dryness to obtain a compound 11;
(10) adding 2, 4-dimethylbenzoic acid and dimethylformamide into toluene, cooling, adding oxalyl chloride, heating for reaction, performing reduced pressure evaporation after the reaction is finished to obtain a yellow oily substance, and dissolving the yellow oily substance into dichloromethane to obtain an acyl chloride solution of dichloromethane;
adding the compound 11 and triethylamine into dichloromethane, performing nitrogen protection, then adding an acyl chloride solution of dichloromethane, performing reduced pressure evaporation after the reaction is finished, and then washing and filtering to obtain a compound 12;
(11) dissolving the compound 12 in dichloromethane, adding a hydrogen chloride solution of methanesulfonic acid or 1, 4-dioxane, stirring at room temperature, carrying out reduced pressure rotary evaporation, and filtering to obtain AR-13324 mesylate or hydrochloride;
preferably, in the step (2), dissolving the compound 4 in anhydrous tetrahydrofuran, cooling to-8 to-12 ℃, slowly adding oxalyl chloride dropwise, and keeping the temperature to obtain acyl chloride; meanwhile, adding an asymmetric synthetic chiral auxiliary into anhydrous tetrahydrofuran, cooling to-78 ℃ by using dry ice acetone, adding n-butyl lithium, keeping the temperature and stirring, then adding acyl chloride, continuously reacting for 1-3 hours, heating to room temperature and stirring overnight; stopping the reaction, removing the tetrahydrofuran solvent, extracting, washing and drying the residue to obtain a crude compound 5, and purifying to obtain a pure compound 5; the molar ratio of the added compound 4 to the asymmetric synthetic chiral auxiliary is 0.8-1.3: 1, and the molar ratio of the compound 4 to oxalyl chloride is 1-2: 1.
In the preferable step (3), dissolving the compound 5 in anhydrous tetrahydrofuran, cooling dry ice acetone to-78 ℃, adding sodium hexamethyldisilazide, and reacting for 0.5-1.5 hours under heat preservation; dissolving the compound 13 in anhydrous tetrahydrofuran, adding the anhydrous tetrahydrofuran into the reaction system, keeping the temperature for reaction for 2-4 hours, naturally heating to room temperature, stirring overnight, removing the solvent tetrahydrofuran after the reaction is completed, extracting, washing and drying residues to obtain a crude compound 6, and purifying to obtain a pure compound 6; the molar ratio of the added compound 5 to the sodium hexamethyldisilazide is 16-17: 20, and the molar ratio of the added compound 5 to the added compound 13 is 17-18: 20.
Preferably, in the step (4), the compound 6 is added into an organic solvent and water, ice water is cooled to 0 ℃, then lithium hydroxide is added, stirring is carried out for reaction for 2.5-3.5 hours, the organic solvent is evaporated out under reduced pressure, then filtration is carried out, and the filtrate is extracted, dried and evaporated to dryness under reduced pressure to obtain a compound 7; the molar ratio of the added compound 6 to the lithium hydroxide is 0.5-1.5: 3, and the volume ratio of the organic solvent to the water is 1-3: 1.
Preferably, in the step (5), the compound 7, 1-hydroxybenzotriazole and triethylamine are added into dry dichloromethane, the mixture is cooled to 0 ℃ under the protection of nitrogen, EDCI is added into the reaction solution, the temperature is raised to room temperature, the mixture is stirred and reacted overnight, then the reaction solution is decompressed and evaporated to dryness until no solvent exists, ice water is added into the residue, the pH value is adjusted to 3-4, and the compound 7A is obtained after extraction and purification; the molar ratio of the added compound 7 to the 1-hydroxybenzotriazole is 0.8-1.3: 1, the molar ratio of the added compound 7 to the EDCI is 0.7-1: 1, and the molar ratio of the compound 7 to the triethylamine is 0.2-0.3: 1.
In the preferable step (6), the molar ratio of the added compound 7A to 6-aminoisoquinoline is 4.5-5.5: 6, and the molar ratio of the added compound 7A to EDCI is 4.5-5.5: 6.
Preferably, in the step (7), the temperature is cooled to 4-6 ℃, and the molar ratio of the added compound 8 to the hydrazine hydrate is 0.05-0.2: 1.
In the preferable step (8), the compound 9 is dissolved in dichloromethane, then triethylamine and di-tert-butyl dicarbonate are added for reaction, and after the reaction is finished, the reaction product is decompressed and evaporated to dryness to obtain a compound 10; the molar ratio of the added compound 9 to triethylamine is 0.06-0.08: 1, and the molar ratio of the added compound 9 to di-tert-butyl dicarbonate is 66-68: 1.
In the step (9), the addition amount of tetrabutylammonium fluoride is not particularly required, and the addition amount is conventional in the art.
Preferably, in the step (10), 2, 4-dimethylbenzoic acid and dimethylformamide are dissolved in toluene, the mixture is cooled to 2-5 ℃, oxalyl chloride is added, the temperature is raised to room temperature, the mixture is stirred overnight, a yellow oily substance is obtained by reduced pressure evaporation, the yellow oily substance is dissolved in dichloromethane to obtain an acyl chloride solution of dichloromethane, and the molar ratio of the added 2, 4-dimethylbenzoic acid to the oxalyl chloride is 9-11: 13;
adding a compound 11 and triethylamine into dichloromethane, protecting with nitrogen, slowly adding an acyl chloride solution of dichloromethane at 0-5 ℃ for reaction, after the reaction is finished, decompressing and evaporating to dryness, then washing and filtering to obtain a compound 12, wherein the molar ratio of the added compound 11 to the added 2, 4-dimethylbenzoic acid is 0.7-0.8: 1.
Preferably, in the step (11), the molar ratio of the compound 12 to the methanesulfonic acid is 0.5-1.5: 3, the molar concentration of hydrogen chloride in the hydrogen chloride solution of 1, 4-dioxane is 3.5-4.5 mol/L, and the molar ratio of the compound 12 to the hydrogen chloride in the hydrogen chloride solution of 1, 4-dioxane is 0.1-0.15: 1.
The organic solvent in the invention can adopt one of 1, 4-dioxane, methanol, ethanol and isopropanol.
Compared with the existing chiral HP L C method or SFC method, the method for preparing the AR-13324 by adopting the chemical synthesis method has the characteristics of simple operation, simple synthesis conditions, low cost, high purity and high yield, and the chiral monomer is obtained.
Drawings
FIG. 1 is a 1HNMR spectrum of AR-13324 hydrochloride.
Detailed Description
The term "T L C" as used herein refers to Thin layer Chromatography (Thin L eye Chromatography), also known as Thin layer Chromatography.
EDCI in the present invention means 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride.
The molar concentration of hydrogen chloride in the hydrogen chloride solution of 1, 4-dioxane means the concentration at which HCl gas is dissolved in 1, 4-dioxane, e.g. a molar concentration of 4 mol/L of hydrogen chloride in the hydrogen chloride solution of 1, 4-dioxane means 4mol of HCl gas is dissolved in 1L dioxane.
The present invention is further illustrated below with reference to examples, and the non-mentioned parts of the present invention are prior art.
Example 1
Synthesis of Compound 2
Dissolving 50g of compound 1 (4-methylphenylacetic acid) in 200ml of carbon tetrachloride, heating to reflux, adding NBS (N-bromosuccinimide) (62g, 0.35mol) in batches under the heating state, continuously keeping the reflux state for 3 hours after the addition, separating out a large amount of solid, wherein T L C shows that the raw materials are completely reacted, cooling the reaction solution to room temperature, pouring the reaction solution into 500 ml of ice water under the stirring state, continuously stirring for 20 minutes, filtering, washing a filter cake for 3 times (300ml each time) with water to obtain white solid, drying the white solid for 10 hours at 50 ℃ to obtain 51g of compound 2 (4-bromomethylphenylacetic acid), and directly carrying out the next reaction of the compound 2 without continuously purifying.
Synthesis of Compound 3
Adding the compound 2(50g) into 200ml of water, stirring and heating to reflux, keeping for 2 hours, performing reverse strain clarification, then cooling to room temperature, cooling to about 2 ℃ in an ice bath, separating out a white solid, filtering, washing a filter cake for 2 times by using water to obtain the white solid, and drying the white solid at 50 ℃ for 10 hours to obtain about 33 g of the compound 3.
Synthesis of Compound 4
Dissolving compound 3(30g) and imidazole (18.5g) in 300ml of DMF, cooling to 0 ℃ in an ice bath, adding TBSCl (32.65g) in batches, naturally heating to room temperature and stirring overnight, wherein T L C shows that the raw materials completely disappear, cooling to about 0 ℃ in the ice bath, quenching the reaction by using a saturated ammonium chloride aqueous solution, adjusting the pH value to 3-4 by using 1M dilute hydrochloric acid, heating to room temperature and stirring for half an hour, extracting for 3 times (200 ml each time) by using methyl tert-butyl ether, combining organic phases, washing with saturated salt solution, drying with anhydrous sodium sulfate, filtering and spin-drying to obtain crude compound 4(46g), and directly using the crude compound in the next reaction without further purification.
Synthesis of Compound 5 (chiral ligand)
Dissolving a compound 4(40g, 142.64mmol) in anhydrous tetrahydrofuran (500 ml), cooling dry ice acetone to-10 ℃, slowly dropwise adding oxalyl chloride (11.0g), and keeping the dropwise adding temperature not higher than-10 ℃ to prepare acyl chloride; meanwhile, 21.16g of (R) -4-phenyl-2-oxazolidinone is added into 500 ml of anhydrous tetrahydrofuran in another three-necked bottle, nitrogen is used for replacement, dry ice acetone is used for cooling to-78 ℃, n-butyl lithium (2.5M, 60ml) is slowly dripped and the temperature is kept at-78 ℃, stirring is continuously carried out for 1 hour at-78 ℃ after dripping is finished, then the prepared acyl chloride is slowly dripped through a constant pressure funnel, the dripping temperature is kept at-78 ℃, reaction is continuously carried out for 2 hours at-78 ℃ after dripping is finished, and then the temperature is naturally raised to room temperature and stirring is carried out overnight. The reaction was quenched with saturated aqueous ammonium chloride, the tetrahydrofuran solvent was removed by rotary evaporation, the residue was extracted 3 times with ethyl acetate (300ml each), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and rotary dried to give crude compound 5, which was purified by column chromatography to give pure compound 5(40.5g) in 73.39% yield.
Synthesis of Compound 6
Dissolving pure compound 5(40g, 94mmol) in anhydrous tetrahydrofuran (400ml), replacing with nitrogen, cooling to-78 ℃ with dry ice acetone, slowly dropwise adding a tetrahydrofuran solution of sodium hexamethyldisilazide (112.8mmol, the concentration of sodium hexamethyldisilazide is 2 mol/L%), stirring at-78 ℃ for 1 hour after dropwise addition is completed, dissolving compound 13(108mmol) in 400ml of anhydrous Tetrahydrofuran (THF), slowly dropwise adding the above system through a constant pressure funnel, controlling the dropwise adding temperature to be lower than-70 ℃, keeping the reaction at-78 ℃ for stirring for 3 hours after the dropwise addition is completed, naturally heating to room temperature and stirring overnight, T L C shows that the raw material is completely reacted, quenching the reaction is carried out with 500 ml of saturated aqueous ammonium chloride solution, removing the solvent tetrahydrofuran by rotary evaporation, extracting the residue with ethyl acetate for 3 times (200 ml each), combining organic phases, washing with saturated water, drying with anhydrous sodium sulfate, filtering and rotary drying to obtain crude compound 6, purifying by column to obtain pure compound 6(43g), and obtaining yield (78.24%).
Synthesis of Compound 7
Adding a pure product of the compound 6(29.2g,0.05mol) into 300ml of tetrahydrofuran and 100ml of water, cooling the reaction system to 0 ℃ by ice water, then adding lithium hydroxide (6.3g,0.15mol), stirring for 3 hours at 0 ℃, L C-MS monitoring the reaction until the compound 6 disappears, distilling off a large amount of white solid from the organic solvent by decompression, filtering, adjusting the pH of the filtrate to 3-4 by using 1N hydrochloric acid aqueous solution at room temperature, extracting by ethyl acetate (100ml) for four times, drying by sodium sulfate, evaporating to dryness by decompression to obtain 20.1g of white foamy solid, directly using in the next step without further purification, wherein the purity is 94.5%.
Synthesis of Compound 7A
Compound 7(22.5g,0.05mol), HOBT (1-hydroxybenzotriazole) (6.75g,0.05mol) and triethylamine (25ml) were added to dry dichloromethane (300ml), cooled to 0 ℃ under nitrogen protection, EDCI (22.5g,0.05mol) was then added to the reaction solution, stirred for a while, the reaction solution became clear, slowly warmed to room temperature, reacted overnight, the reaction solution was evaporated to dryness under reduced pressure to be solvent-free, 200ml of ice water was added to the residue, pH was adjusted to 2-3 with ice-cooled aqueous hydrochloric acid solution, EA extraction, column purification (dichloromethane: methanol ═ 20:1-10:1) gave compound 7A (18.65g) as a white foamy solid with yield 85%, L C-MS (M-1) 438.
Synthesis of Compound 8
Compound 7A (10.9g,25mmol), 6-aminoisoquinoline (4.32g,30mmol) and EDCI (6.68g,35mmol) were added to pyridine (100ml) at room temperature under nitrogen blanket, then DMAP (4-dimethylaminopyridine) (4.2g,35mmol) was added and reacted overnight, T L C (DCM: MA ═ 20:1) was monitored for reaction until the starting compound 7A disappeared, evaporated to dryness under reduced pressure, 3 moles of aqueous acetic acid was adjusted to pH 4-5, DCM (100ml ═ 4) was extracted and combined over the column to give compound 8(11.02g) in 78% yield and L C-MS (M +1)566 with purity: 97.4%.
Synthesis of Compound 9
Compound 8(11.02g,19.5mmol) was dissolved in ethanol (100ml), hydrazine hydrate (85%, 9.75g,195mmol) was added thereto, heated to reflux, a large amount of white solid was formed after about 2 hours, then the reaction was continued for 3 hours, cooled to 5 degrees, filtered, the filter cake was washed with cold ethanol, evaporated to dryness under reduced pressure, and reduced to no solvent with an oil pump to give compound 9(11.4g) which was used directly in the next step.
Synthesis of Compound 10
The compound 9(11.4g,19.5mmol) obtained in the above step was dissolved in 100ml of dichloromethane, triethylamine (10ml) was then added thereto, and (BOC)2O (di-tert-butyl dicarbonate) (6.4g,0.29mmol) was slowly added dropwise with a large amount of gas evolved, T L C (ethyl acetate) was monitored until the compound 9 disappeared, evaporated to dryness under reduced pressure, and column chromatography (EA: PE ═ 1:1) was performed to obtain a white solid product (9.49g), which was the compound 10, with a yield of 90%.
Synthesis of Compound 11
The compound 10 obtained in the previous step (8g,15mmol) was added to 100ml THF (tetrahydrofuran) and tetrabutylammonium fluoride (7.83g,30mmol) was added thereto, stirred overnight, T L c (EA) was checked for the absence of compound 10, evaporated to dryness under reduced pressure, 200ml water was added to the residue, stirred for 30min, allowed to stand for a period of time, water was decanted, the tan oil was dissolved in sodium sulfate in EA and dried, the organic solvent was removed to give compound 11(7.86g) which was used in the next step for further processing.
Synthesis of Compound 12
Adding 2, 4-dimethylbenzoic acid (1.5g and 10mmol) and a catalytic amount of DMF (dimethyl formamide) into toluene, cooling to 2-5 ℃, dropwise adding oxalyl chloride (1.64g and 13mmol), heating to room temperature after dropwise adding, stirring overnight, gradually dissolving a solid in the process to obtain a clear liquid, evaporating to dryness under reduced pressure to obtain a yellow oily substance, and dissolving with dichloromethane (10ml) to obtain an acyl chloride solution of dichloromethane;
adding compound 11(3.2g,7.7mmol) and triethylamine (2ml) into 20ml dichloromethane, adding dropwise the prepared dichloromethane solution at 0-5 ℃ under nitrogen protection, stirring after adding, reacting overnight, monitoring the reaction with T L C (dichloromethane: methanol 20:1), evaporating to dryness under reduced pressure after the reaction is finished, stirring with saturated sodium carbonate solution, filtering, washing the filter cake with water for 3 times, and drying to obtain 3.9g white solid, namely compound 12, with the purity of 99.1%, the optical purity of 100% (CHIRA L PAK AS-H, 0.46cm I.D, × 15cm L +0.1DEA)/CO2 ═ 20/80(V/V, 2.0ml/min), R typet3.253 min; s type Rt＝4.3min)。
Adding compound 12(3.9g) into DCM, stirring to obtain clear solution, adding 1, 4-dioxane hydrogen chloride solution 15ml (concentration is 4 mol/L, 4mol HCl gas is dissolved in 1L dioxane) dropwise, stirring at room temperature for 4 hours, carrying out reduced pressure rotary evaporation and filtration to obtain 3.65g of white solid product, and detecting the obtained product by HNMR, namely AR-13324 hydrochloride, wherein the 1HNMR spectrogram is shown in figure 1, MS, purity, 99.4%, 1HNMR (400MHz, DMSO, 300) (ppm), 11.773(s,1H),9.702(s,1H),8.740(d,1H),8.560(d,1H),8.469(d,1H),8.360(d,1H),8.280(s,3H),8.158(dd,1H),7.777(d,1H),7.577(d,2H), 6326 (d,2H),7.134(s,1H), 5963H, 5.281 (d, 638H), 5963H, 638 (d, 3H), 5963H), 5.281 (d,1H), 638H, 2H, 5.281, 2H, 638H, 5.281H, and so as the like.
The structural formula of AR-13324 hydrochloride is as follows:
example 2
In this example, the same procedure as in example 1 was repeated except that the treatment step of Compound 12 was different.
The procedure for treatment of compound 12 was as follows: dissolving the compound 12(3.9g) in 40ml of dichloromethane, then dropwise adding methanesulfonic acid (2g, 21.6mmol), stirring at room temperature overnight, carrying out rotary evaporation under reduced pressure, adding 100ml of diethyl ether, stirring to generate a large amount of white solid, filtering, and drying to obtain a white solid (4.54g), wherein the yield is 97.8%, the purity is 98.2%, and the substance obtained is AR-13324 methanesulfonate detected by 1 HNMR.
Example 3
In this example, the procedure was the same as in example 1 except that the synthesis procedure of Compound 5 was different.
Synthesis of Compound 5A (chiral ligand)
Dissolving compound 4(50g, 178.3mmol) in anhydrous tetrahydrofuran (500 ml), cooling to-10 ℃ with dry ice acetone, slowly dropping oxalyl chloride (13g), keeping the dropping temperature not higher than-10 ℃ to obtain acyl chloride, simultaneously adding 28.7g of (R) -4-benzyl-2-oxazolidinone into 500 ml anhydrous tetrahydrofuran in another three-necked flask, replacing with nitrogen, cooling to-78 ℃ with dry ice acetone, slowly dropping 7.2ml of n-butyllithium solution (with the concentration of 2.5 mol/L) and keeping the temperature at-78 ℃, continuing stirring at-78 ℃ for 1 hour after dropping, slowly dropping the prepared acyl chloride into the three-necked flask through a constant pressure funnel, keeping the dropping temperature at-78 ℃, continuing to keep the reaction at-78 ℃ for 2 hours after dropping, then naturally heating to room temperature, stirring, quenching the reaction with saturated ammonium chloride water solution, distilling off the tetrahydrofuran solvent, extracting the residue with ethyl acetate for 3 times (300 times), washing with water, merging saturated sodium sulfate, obtaining a crude product (355 g) and filtering with pure sodium sulfate to obtain a crude product (355 g).
The synthetic route of example 3 is as follows:
Claims (8)
1. a preparation method of AR-13324 mesylate or hydrochloride is characterized in that chiral ligand is used for chiral induction synthesis of the mesylate or hydrochloride, and comprises the following steps:
(1) protecting hydroxyl in 4- (hydroxymethyl) phenylacetic acid by TBSCl to obtain a crude compound 4;
(2) dissolving the compound 4 in anhydrous tetrahydrofuran, cooling to-8-12 ℃, slowly dripping oxalyl chloride, and keeping the temperature to obtain acyl chloride; meanwhile, adding an asymmetric synthetic chiral auxiliary into anhydrous tetrahydrofuran, cooling to-78 ℃ by using dry ice acetone, adding n-butyl lithium, keeping the temperature and stirring, then adding acyl chloride, continuously reacting for 1-3 hours, heating to room temperature and stirring overnight; terminating the reaction, removing the tetrahydrofuran solvent, extracting, washing and drying the residue to obtain a crude compound 5, and purifying to obtain a pure compound 5, wherein the compound 5 is a chiral ligand; the structural formula of the compound 5 is shown as the formula 5:
(3) dissolving the compound 5 in anhydrous tetrahydrofuran, cooling dry ice acetone to-78 ℃, adding sodium hexamethyldisilazide, and reacting for 0.5-1.5 hours under the condition of heat preservation; dissolving the compound 13 in anhydrous tetrahydrofuran, adding the anhydrous tetrahydrofuran into the reaction system, keeping the temperature for reaction for 2-4 hours, naturally heating to room temperature, stirring overnight, removing the solvent tetrahydrofuran after the reaction is completed, extracting, washing and drying residues to obtain a crude compound 6, and purifying to obtain a pure compound 6;
(4) adding the compound 6 into an organic solvent and water, cooling by ice water, adding lithium hydroxide, stirring for reaction, evaporating the organic solvent under reduced pressure, filtering, extracting the filtrate, drying, and evaporating to dryness under reduced pressure to obtain a compound 7;
(5) adding the compound 7, 1-hydroxybenzotriazole and triethylamine into dry dichloromethane, carrying out nitrogen protection, cooling, adding EDCI into a reaction solution, heating and stirring, then carrying out reduced pressure evaporation on the reaction solution until no solvent exists, adding ice water into a residue, adjusting pH, extracting and purifying to obtain a compound 7A;
(6) adding the compound 7A, 6-aminoisoquinoline and EDCI into pyridine, performing nitrogen protection, then adding 4-dimethylaminopyridine, reacting overnight, and performing reduced pressure evaporation to obtain a compound 8 after complete reaction;
(7) dissolving the compound 8 in an organic solvent, adding hydrazine hydrate into the organic solvent, heating the mixture to reflux, cooling the mixture after the reaction is finished, and filtering the mixture to obtain a compound 9;
(8) introducing tert-butyloxycarbonyl to protect amino in the compound 9 to obtain a compound 10;
(9) adding the compound 10 into an organic solvent, then adding tetrabutylammonium fluoride for reaction, and after the reaction is finished, decompressing and evaporating to dryness to obtain a compound 11;
(10) adding 2, 4-dimethylbenzoic acid and dimethylformamide into toluene, cooling, adding oxalyl chloride, heating for reaction, performing reduced pressure evaporation after the reaction is finished to obtain a yellow oily substance, and dissolving the yellow oily substance into dichloromethane to obtain an acyl chloride solution of dichloromethane;
adding the compound 11 and triethylamine into dichloromethane, performing nitrogen protection, then adding an acyl chloride solution of dichloromethane, performing reduced pressure evaporation after the reaction is finished, and then washing and filtering to obtain a compound 12;
(11) dissolving the compound 12 in dichloromethane, adding a hydrogen chloride solution of methanesulfonic acid or 1, 4-dioxane, stirring at room temperature, carrying out reduced pressure rotary evaporation, and filtering to obtain AR-13324 mesylate or hydrochloride;
2. the preparation method according to claim 1, wherein in the step (2), the molar ratio of the compound 4 to the asymmetric synthetic chiral auxiliary is 0.8-1.3: 1, and the molar ratio of the compound 4 to oxalyl chloride is 1-2: 1.
3. The method according to claim 2, wherein in the step (3), the molar ratio of the compound 5 to the sodium hexamethyldisilazide is 16 to 17:20, and the molar ratio of the compound 5 to the compound 13 is 17 to 18: 20.
4. The preparation method according to claim 3, wherein in the step (4), the compound 6 is added into an organic solvent and water, ice water is cooled to 0 ℃, then lithium hydroxide is added, stirring is carried out for reaction for 2.5-3.5 hours, the organic solvent is evaporated out under reduced pressure, then the organic solvent is filtered, and the filtrate is extracted, dried and evaporated to dryness under reduced pressure to obtain a compound 7; the molar ratio of the added compound 6 to the lithium hydroxide is 0.5-1.5: 3, and the volume ratio of the organic solvent to the water is 1-3: 1.
5. The preparation method according to claim 4, wherein in the step (5), the compound 7, 1-hydroxybenzotriazole and triethylamine are added into dry dichloromethane, nitrogen is used for protection, the temperature is reduced to 0 ℃, EDCI is added into the reaction solution, the temperature is increased to room temperature, stirring is carried out, the reaction is carried out overnight, then the reaction solution is decompressed and evaporated to dryness until no solvent exists, ice water is added into the residue, the pH is adjusted to 3-4, and the compound 7A is obtained through extraction and purification; the molar ratio of the added compound 7 to the 1-hydroxybenzotriazole is 0.8-1.3: 1, the molar ratio of the added compound 7 to the EDCI is 0.7-1: 1, and the molar ratio of the compound 7 to the triethylamine is 0.2-0.3: 1.
6. The method according to claim 5, wherein in the step (7), the cooling is performed to 4 to 6 ℃, and the molar ratio of the compound 8 to the hydrazine hydrate is 0.05 to 0.2: 1.
7. The preparation method according to claim 6, characterized in that in the step (8), the compound 9 is dissolved in dichloromethane, then triethylamine and di-tert-butyl dicarbonate are added for reaction, and after the reaction is completed, the reaction product is evaporated to dryness under reduced pressure to obtain a compound 10; the molar ratio of the added compound 9 to triethylamine is 0.06-0.08: 1, and the molar ratio of the added compound 9 to di-tert-butyl dicarbonate is 66-68: 1.
8. The preparation method according to claim 7, wherein in the step (10), 2, 4-dimethylbenzoic acid and dimethylformamide are dissolved in toluene, the mixture is cooled to 2-5 ℃, oxalyl chloride is added, the temperature is raised to room temperature, the mixture is stirred overnight, reduced pressure is evaporated to dryness to obtain yellow oily matter, the yellow oily matter is dissolved in dichloromethane to obtain an acyl chloride solution of dichloromethane, and the molar ratio of the added 2, 4-dimethylbenzoic acid to the oxalyl chloride is 9-11: 13;
adding a compound 11 and triethylamine into dichloromethane, protecting with nitrogen, slowly adding an acyl chloride solution of dichloromethane at 0-5 ℃ for reaction, after the reaction is finished, decompressing and evaporating to dryness, then washing and filtering to obtain a compound 12, wherein the molar ratio of the added compound 11 to the added 2, 4-dimethylbenzoic acid is 0.7-0.8: 1.
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| WO2000049020A2 (en) * | 1999-02-18 | 2000-08-24 | Schering Aktiengesellschaft | Novel epothilon derivatives, method for the production thereof and their pharmaceutical application |
| WO2010098332A1 (en) * | 2009-02-26 | 2010-09-02 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | Method for producing polycyclic compound and intermediate for same |
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