CN107434780A - Preparation method of AR-13324 - Google Patents

Preparation method of AR-13324 Download PDF

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CN107434780A
CN107434780A CN 201610356984 CN201610356984A CN107434780A CN 107434780 A CN107434780 A CN 107434780A CN 201610356984 CN201610356984 CN 201610356984 CN 201610356984 A CN201610356984 A CN 201610356984A CN 107434780 A CN107434780 A CN 107434780A
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李钰
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上海韬勤生物医药科技有限公司
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D217/00Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02Heterocyclic 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
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D263/00Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08Heterocyclic 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
    • C07D263/16Heterocyclic 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
    • C07D263/18Oxygen atoms
    • C07D263/20Oxygen atoms attached in position 2
    • C07D263/26Oxygen atoms attached in position 2 with hetero atoms or acyl radicals directly attached to the ring nitrogen atom

Abstract

The invention relates to a preparation method of AR-13324. According to the invention, a chiral ligand is used for chiral induced synthesis of AR-13324. In comparison with an existing chiral HPLC method or a SFC method, the method of the invention has the following beneficial effects: the AR-13324 prepared by the chemical synthetic method has characteristics of simple operation, simple synthetic condition and low cost; a high-purity chiral monomer is obtained; and yield is high.

Description

一种AR-13324的制备方法 A method for preparation of AR-13324

技术领域 FIELD

[0001 ]本发明涉及医药领域,具体涉及ROCK激酶和去甲肾上腺素转运体抑制剂,更具体的涉及AR-13324抑制剂的制备方法。 [0001] The present invention relates to the field of medicine, particularly to ROCK kinase and norepinephrine transporter inhibitors, and more particularly relates to a method for preparing inhibitor AR-13324.

背景技术 Background technique

[0002] AR-13324是ROCK激酶和去甲肾上腺素转运体抑制剂。 [0002] AR-13324 ROCK kinases and are norepinephrine transporter inhibitors. 现有方法中通常通过手性HPLC法或者SFC法进行制备,HPLC法是目前的常用方法,但手性固定相的成本太高,手性流动相添加剂使色谱条件复杂化;采用SFC(超临界流体色谱)制备AR-13324存在同样的问题, 不仅成本高、而且收率还低。 In the conventional method is generally carried out by chiral HPLC or SFC method preparation method, the HPLC method is a common method, but the cost is too high chiral stationary phase, chiral mobile phase additive complicate chromatographic conditions; using SFC (supercritical fluid chromatography) AR-13324 prepared in the presence of the same problem is not only costly, but also the yield is low.

发明内容 SUMMARY

[0003] 本发明的目的在于提供一种操作简单、成本低的AR-13324的制备方法。 [0003] The object of the present invention is to provide a simple, inexpensive method for preparing AR-13324 operation.

[0004] 本发明的具体技术方案如下: [0004] The particular aspect of the present invention is as follows:

[0005] —种AR-13324的制备方法,利用手性配体手性诱导合成AR-13324,手性配体的结构式如式5所示: [0005] - AR-13324 preparation methods utilizing chiral ligand chiral AR-13324 induces the synthesis, structural formula of chiral ligands as shown in Formula 5:

[0006] [0006]

Figure CN107434780AD00071

X为OTBS、OTIPS,Y 为Ph、Bn、t-bu、4-硝基苯基或4-甲氧基苯.··. ,. 基,A为氧或硫。 X is OTBS, OTIPS, Y is Ph, Bn, t-bu, 4- nitrophenyl or 4-methoxybenzyl. ··.,. Yl, A is oxygen or sulfur.

[0007] 优选的手性配体的合成步骤如下: [0007] The synthetic procedure is preferred chiral ligands of the following:

Figure CN107434780AD00072

[0008] (1)通过TBSCl或TIPSCl对4-(羟基甲基)苯乙酸中的羟基进行保护,得到粗品化合物4; [0008] (1) Protection of 4- (hydroxymethyl) phenylacetic acid or the hydroxyl group by TBSCl TIPSCl, to give crude compound 4;

[0009] X为0TBS、0TIPS, [0009] X is 0TBS, 0TIPS,

[0010] (2)将化合物4、不对称合成手性助剂溶于有机溶剂中,加入草酰氯,干冰丙酮降温,在催化剂作用下反应得到手性配体,手性配体的结构式如式5所示: [0010] (2) Compound 4, asymmetric synthesis of the chiral auxiliary in an organic solvent, was added oxalyl chloride, dry ice-acetone cooling, the reaction to give a chiral ligand of formula, as chiral ligands in the catalyst of formula Figure 5:

[0011] [0011]

Figure CN107434780AD00073

X为OTBS、OTIPS,Y为Ph、Bn、t-bu、4-硝基苯基或4-甲氧基苯基,A为氧或硫。 X is OTBS, OTIPS, Y is Ph, Bn, t-bu, 4- nitrophenyl or 4-methoxyphenyl, A is oxygen or sulfur.

[0012] 优选的利用手性配体手性诱导合成AR-13324包括如下步骤: [0012] Preferred chiral ligands by chiral synthesis induced AR-13324 comprising the steps of:

[0013] (1)通过TBSC1或TI PSCl对4-(羟基甲基)苯乙酸中的羟基进行保护,得到粗品化合物4; [0013] (1) Protection of 4- (hydroxymethyl) phenylacetic acid or the hydroxyl group by TBSC1 TI PSCl, to give crude compound 4;

Figure CN107434780AD00081

[0014] X为0TBS、0TIPS, [0014] X is 0TBS, 0TIPS,

[0015] (2)将化合物4、不对称合成手性助剂溶于有机溶剂中,加入草酰氯,干冰丙酮降温,在催化剂作用下反应得到手性配体,手性配体的结构式如式5所示: [0015] (2) Compound 4, asymmetric synthesis of the chiral auxiliary in an organic solvent, was added oxalyl chloride, dry ice-acetone cooling, the reaction to give a chiral ligand of formula, as chiral ligands in the catalyst of formula Figure 5:

[0016]X为0TBS、0TIPS,Y为?11、811、卜1311、4-硝基苯基或4-甲氧基苯 [0016] X is 0TBS, 0TIPS, Y is? 11,811, Bu 1311,4- nitrophenyl or 4-methoxybenzyl

Figure CN107434780AD00082

, 基,A为氧或硫, , Group, A is oxygen or sulfur,

[0017] (3)将化合物5、六甲基二硅胺钠、化合物13溶于有机溶剂中,干冰丙酮降温,搅拌反应,然后升温至室温并搅拌过夜,得到粗品化合物6,过柱纯化得到纯品化合物6; [0017] (3) The compound 5, sodium hexamethyldisilazane amine, compound 13 is dissolved in an organic solvent, a dry ice acetone cooling, the reaction was stirred, then warmed to room temperature and stirred overnight to give the crude compound 6, was purified by column to give pure compound 6;

[0018] [0018]

Figure CN107434780AD00083

[0019] [0019]

Figure CN107434780AD00084

X为0TBS、0TIPS,Y为卩11、811、卜1311、4-硝基苯基或4-甲氧基苯基,A为氧或硫, X is 0TBS, 0TIPS, Y is Jie 11,811, Bu 1311,4- nitrophenyl or 4-methoxyphenyl, A is oxygen or sulfur,

[0020] (4)将化合物6加入有机溶剂和水中,冰水冷却,然后加入氢氧化锂,搅拌反应,调节PH值,减压蒸出有机溶剂、然后过滤,滤液经萃取、干燥、减压蒸干得到化合物7; [0020] (4) Compound 6 is added an organic solvent and water, ice-water cooling, followed by addition of lithium hydroxide, the reaction was stirred, PH adjustment values, the organic solvent was distilled off under reduced pressure, and then filtered, and the filtrate was extracted, and dried under reduced pressure evaporated to dryness to obtain compound 7;

[0021] [0021]

Figure CN107434780AD00085

X为0TBS、0TIPS X is 0TBS, 0TIPS

[0022] (5)将化合物7、1-羟基苯并三唑、三乙胺加入到干燥二氯甲烷中,氮气保护,降温, 向反应液中加入EDCI,升温搅拌,然后将反应液减压蒸干至无溶剂,向残余物中加入冰水, 调节pH,经萃取、纯化得到化合物7A; [0022] (5) The compound 7,1- hydroxybenzotriazole, triethylamine were added to dry dichloromethane, nitrogen, cooling, EDCI was added to the reaction mixture was heated with stirring, then the reaction mixture under reduced pressure until no solvent was evaporated to dryness, to the residue was added ice-water, the pH adjusted, by extraction, to give compound. 7A;

[0023] [0023]

Figure CN107434780AD00091

X为0TBS、0TIPS X is 0TBS, 0TIPS

[0024] (6)将化合物7A、6_氨基异喹啉和EDCI加入吡啶中,氮气保护,然后加入4-二甲氨基吡啶,反应过夜,反应完全后减压蒸干得到化合物8; [0024] (6) Compound 7A, 6_ aminoisoquinoline and EDCI was added pyridine nitrogen, followed by the addition of 4-dimethylaminopyridine, the reaction overnight, the reaction was complete and evaporated to dryness under reduced pressure to give Compound 8;

[0025] [0025]

Figure CN107434780AD00092

X为0TBS、0TIPS, X is 0TBS, 0TIPS,

[0026] (7)将化合物8溶于有机溶剂中,向其中加入水合肼,加热至回流,反应完成后冷却,过滤,得到化合物9; [0026] (7) Compound 8 is dissolved in an organic solvent, to which was added hydrazine hydrate and heated to reflux, cooled after completion of the reaction, was filtered to give compound 9;

[0027] [0027]

Figure CN107434780AD00093

X为0TBS、0TIPS, X is 0TBS, 0TIPS,

[0028] (8)引入叔丁氧羰基对化合物9中的氨基进行保护,得到化合物10; [0028] (8) introduced into the t-butoxycarbonyl group in compound 9 to protect the amino group, to give compound 10;

Figure CN107434780AD00094

[0029] X为0TBS、0TIPS, :? [0029] X is 0TBS, 0TIPS,:?

[0030] (9)将化合物10加入有机溶剂中,然后加入四丁基氟化氨进行反应,反应完成后减压蒸干,得到化合物11; [0030] (9) Compound 10 is added an organic solvent, followed by addition of tetrabutylammonium fluoride ammonia reaction, evaporated to dryness under reduced pressure after the completion of the reaction, to give compound 11;

Figure CN107434780AD00095

[0032] (10)将2,4_二甲基苯甲酸和二甲基甲酰胺加于甲苯中,冷却,加入草酰氯,升温反应、反应完成后减压蒸干得到黄色油状物、将其溶于二氯甲烷中得到二氯甲烷的酰氯溶液; [0032] (10) The 2,4_ dimethyl benzoic acid and dimethyl formamide was added to the toluene and cooled, was added oxalyl chloride, heating the reaction, after the completion of the reaction evaporated to dryness under reduced pressure to give a yellow oil, which was dissolved in methylene chloride to give the acid chloride solution in dichloromethane;

[0033] 将化合物11、三乙胺、加入到二氯甲烷中,氮气保护,然后加入二氯甲烷的酰氯溶液,反应完成后减压蒸干,然后经洗涤、过滤后得到化合物12; [0033] Compound 11, triethylamine was added to the methylene chloride, a nitrogen atmosphere, followed by addition of the acid chloride in dichloromethane, evaporated to dryness under reduced pressure after the completion of the reaction, and then washed, filtered to obtain compound 12;

Figure CN107434780AD00101

[0035] (11)将化合物12溶于二氯甲烷中,然后加入甲磺酸或1,4_二氧六环的氯化氢溶液于室温下搅拌,减压旋蒸、过滤得到AR-13324甲磺酸盐或者盐酸盐; [0035] (11) Compound 12 was dissolved in dichloromethane, followed by addition of methanesulfonic acid or hydrogen chloride 1,4_-dioxane was stirred at room temperature, rotary evaporated under reduced pressure, filtered to give methanesulfonamide AR-13324 or a hydrochloride salt;

Figure CN107434780AD00102

[0037] 优选的步骤(2)中,将化合物4溶于无水四氢呋喃中,降温至-8〜_12°C,缓慢滴加草酰氯,保温,得到酰氯;同时另外将不对称合成手性助剂加入无水四氢呋喃中,用干冰丙酮降温至_78°C,加入正丁基锂,保温搅拌,然后加入酰氯继续反应1〜3小时,升温至室温搅拌过夜;终止反应,除去四氢呋喃溶剂,残留物经萃取、洗涤、干燥得到粗品化合物5,纯化后得到纯品化合物5;加入的化合物4与不对称合成手性助剂的摩尔比为0.8〜1.3:1,化合物4 与草酰氯的摩尔比为1〜2:1。 [0037] Preferably step (2), Compound 4 was dissolved in dry tetrahydrofuran, cooled to -8~_12 ° C, was slowly added dropwise oxalyl chloride, insulation, to give the acid chloride; while the other asymmetric synthesis of chiral auxiliary is added anhydrous tetrahydrofuran, cooled to _78 ° C with dry ice-acetone, was added n-butyl lithium, keep stirring, followed by addition of the acid chloride the reaction was continued 1 ~ 3 hours, allowed to warm to room temperature and stirred overnight; termination of the reaction, tetrahydrofuran solvent was removed, and the residue product was extracted, washed, and dried to give crude compound 5, compound 5 to give the pure product after purification; compound added 4 molar ratio of asymmetric synthesis and chiral auxiliaries is 0.8~1.3: 1, molar ratio of compound 4 with oxalyl chloride is ~ 2: 1.

[0038] 优选的步骤(3)中,将化合物5溶入无水四氢呋喃中,干冰丙酮降温降温至_78°C 度,加入六甲基二硅胺钠保温反应0.5〜1.5小时;将化合物13溶于无水四氢呋喃后加入前述反应体系中,保温反应2〜4小时,自然升温至室温并搅拌过夜,反应完全后除去溶剂四氢呋喃,残留物经萃取、洗涤、干燥得到粗品化合物6,纯化后得到纯品化合物6;加入的化合物5与六甲基二硅胺钠的摩尔比为16〜17:20,加入的化合物5与化合物13的摩尔比为17〜18: 20 〇 [0038] Preferably in step (3), the compound 5 dissolved in dry tetrahydrofuran, cooled to dry ice-acetone cooling of _78 ° C, was added sodium hexamethyldisilazide amine reaction was incubated 0.5~1.5 hours; Compound 13 was added dissolved in dry tetrahydrofuran and after the reaction system, the reaction was kept ~ 4 hours, allowed to warm to rt naturally and stirred overnight, the reaction was completed the solvent was removed tetrahydrofuran, the residue was extracted, washed, and dried to give crude compound 6 after purification to give pure compound 6; the molar ratio of compound 5 was added with sodium hexamethyldisilazide amines 16~17: 20, compound 5 is added 13 molar ratio of the compound of 17~18: 20 square

[0039] 优选的步骤(4)中,将化合物6加入有机溶剂和水中,冰水冷却至(TC,然后加入氢氧化锂搅拌反应2.5〜3.5小时,减压蒸出有机溶剂、然后过滤,滤液经萃取、干燥、减压蒸干得到化合物7;加入的化合物6与氢氧化锂的摩尔比为0.5〜1.5:3,有机溶剂与水的体积比为1〜3:1〇 [0039] Preferably step (4), the compound 6 is added an organic solvent and water, cooled to ice-water (the TC, followed by addition of lithium hydroxide was stirred 2.5~3.5 hours, the organic solvent was distilled off under reduced pressure, and then filtered, and the filtrate It was extracted, dried, and evaporated to dryness under reduced pressure to give compound 7; molar ratio of the added compound 6 with lithium hydroxide is 0.5~1.5: 3, volume ratio of organic solvent to water is 1 ~ 3: 1〇

[0040] 优选的步骤(5)中,将化合物7、1_羟基苯并三唑、三乙胺加入到干燥二氯甲烷中, 氮气保护,降温至(TC,向反应液中加入EDCI,升温至室温搅拌,反应过夜,然后将反应液减压蒸干至无溶剂,向残余物中加入冰水,调节PH至3-4,经萃取、纯化得到化合物7A;加入的化合物7与1-羟基苯并三唑的摩尔比为0.8〜1.3:1,加入的化合物7与EDCI的摩尔比为0.7 〜1:1,化合物7与三乙胺的摩尔比为0.2〜0.3:1。 [0040] Preferably step (5), the compound 7,1_-hydroxybenzotriazole, triethylamine were added to dry dichloromethane in a nitrogen atmosphere, cooled to (the TC, EDCI was added to the reaction mixture, warmed to stirring at room temperature overnight, the reaction solution was then evaporated to dryness under reduced pressure until no solvent, to the residue was added ice-water, adjusted to PH 3-4, by extraction, to give compound. 7A; compound 7 was added 1-hydroxy molar ratio of benzotriazole to 0.8~1.3: 1, compound 7 was added EDCI molar ratio of 0.7 ~ 1: 1, molar ratio of compound 7 with triethylamine is 0.2~0.3: 1.

[0041 ]优选的步骤(6)中,加入的化合物7A与6-氨基异喹啉的摩尔比为4.5〜5.5:6,加入的化合物7A与EDCI的摩尔比为4.5〜5.5:6。 [0041] Preferably step (6) was added to 6-amino compound 7A isoquinoline 4.5~5.5 molar ratio: 6, the molar ratio of compound 7A with the addition of EDCI was 4.5~5.5: 6.

[0042] 优选的步骤(7)中,冷却至4〜6°C,加入的化合物8与水合肼的摩尔比为0.05〜 0.2:1。 In [0042] Preferably step (7) and cooled to 4~6 ° C, the added compound 8 molar ratio of hydrazine hydrate 0.05~ 0.2: 1.

[0043] 优选的步骤(8)中,将化合物9溶于二氯甲烷中,然后加入三乙胺和二碳酸二叔丁酯进行反应,反应完成后减压蒸干,得到化合物10;加入的化合物9与三乙胺的摩尔比为0.06〜0.08:1,加入的化合物9与二碳酸二叔丁酯的摩尔比为66〜68:1。 [0043] Preferably step (8), the compound 9 dissolved in methylene chloride, followed by addition of triethylamine and di-tert-butyl dicarbonate is reacted, after the completion of the reaction was evaporated to dryness under reduced pressure, to give compound 10; added compound 9 molar ratio of triethylamine to 0.06~0.08: 1, the molar ratio of the compound 9 was added with di-tert-butyl ester of 66~68: 1.

[0044] 步骤(9)中,对四丁基氟化氨的加入量没有特别要求,采用本领域内常规加入量即可。 [0044] Step (9), there is no special requirements for the amount of tetrabutyl ammonium fluoride was added, the conventional art can be added in an amount.

[0045] 优选的步骤(10)中,将2,4_二甲基苯甲酸和二甲基甲酰胺溶于甲苯中,冷却至2-5 tC,加入草酰氯后升温到室温,搅拌过夜,减压蒸干得到黄色油状物、将其溶于二氯甲烷中得到二氯甲烷的酰氯溶液,加入的2,4-二甲基苯甲酸与草酰氯的摩尔比为9〜11:13; In [0045] Preferably step (10), the 2,4_ dimethyl benzoic acid and dimethyl formamide was dissolved in toluene and cooled to 2-5 tC, after addition of oxalyl chloride was warmed to room temperature and stirred overnight. evaporated to dryness under reduced pressure to give a yellow oil, and the resulting acid chloride solution in dichloromethane is dissolved in dichloromethane, the molar ratio of 2,4-dimethyl benzoic acid with oxalyl chloride added is 9~11: 13;

[0046] 将化合物11、三乙胺加入到二氯甲烷中,氮气保护,然后于0_5°C缓慢加入二氯甲烷的酰氯溶液进行反应,反应完成后减压蒸干,然后经洗涤、过滤后得到化合物12,加入的化合物11与加入的2,4-二甲基苯甲酸的摩尔比为0.7〜0.8:1。 After [0046] Compound 11, triethylamine were added to methylene chloride, nitrogen, and then was slowly added to the acid chloride 0_5 ° C dichloromethane were reacted, after completion of the reaction evaporated to dryness, then washed, filtered to give compound 12, and the molar ratio of added 2,4-dimethyl-benzoic acid compound 11 is added 0.7~0.8: 1.

[0047] 优选的步骤(I 1)中,加入的化合物12与甲磺酸的摩尔比为0.5〜1.5:3;1,4-二氧六环的氯化氢溶液中氯化氢的摩尔浓度为3.5〜4.5moI/L;化合物12与1,4-二氧六环的氯化氢溶液中氯化氢的摩尔比为0.1〜0.15:1。 [0047] Preferably in step (I 1), the compound 12 is added with the molar ratio of methanesulfonic acid is 0.5~1.5: 3; the molar concentration of hydrogen chloride in 1,4-dioxane solution of hydrogen chloride in ring 3.5~4.5 moI / L; molar ratio of compound 12 with a solution of hydrogen chloride in 1,4-dioxane in hydrogen chloride is 0.1~0.15: 1.

[0048] 本发明中的有机溶剂可采用1,4-二氧六环,甲醇,乙醇,异丙醇中的一种。 [0048] In the present invention, the organic solvent can be 1,4-dioxane, methanol, ethanol, isopropanol kind.

[0049] 本发明利用手性配体手性诱导合成AR-13324,与现有的手性HPLC法或者SFC法相比,采用化学合成的方法制备得到AR-13324具有操作简单、合成条件简单、成本低的特点, 高纯度获得手性单体,并且收率高。 [0049] The use of chiral ligands of the present invention induce the synthesis of chiral AR-13324, compared with the conventional method of chiral HPLC or SFC method, a chemical synthesis method for the preparation of AR-13324 obtained is simple, easy synthesis conditions, the cost of low characteristics obtained in high purity chiral monomers, and yield.

附图说明 BRIEF DESCRIPTION

[0050] 图1为AR-13324盐酸盐的IHNMR谱图。 [0050] FIG. 1 is a IHNMR spectrum hydrochloride AR-13324.

具体实施方式 Detailed ways

[0051] 本发明所述的“TLCT指薄层色谱(Thin Layer Chromatography),又称薄层层析。 [0051] "TLCT means that the present invention TLC (Thin Layer Chromatography), also known as thin layer chromatography.

[0052] 本发明中的EDCI指1-(3-二甲氨基丙基)-3_乙基碳二亚胺盐酸盐。 [0052] In the present invention, EDCI refers to 1- (3-dimethylaminopropyl) -3_ ethylcarbodiimide hydrochloride.

[0053] 1,4_二氧六环的氯化氢溶液中氯化氢的摩尔浓度指的是将HCl气体溶解在1,4_二氧六环中的浓度,如1,4-二氧六环的氯化氢溶液中氯化氢的摩尔浓度为4mo 1/L指4moI HCl 气体溶于IL二氧六环。 Molar concentration of hydrogen chloride [0053] 1,4_ hydrogen chloride in dioxane refers to the concentration of HCl gas dissolved in dioxane 1,4_, such as hydrogen chloride in 1,4-six rings molar solution of hydrogen chloride was 4mo 1 / L refers 4moI HCl gas dissolved in dioxane IL.

[0054] 以下结合实施例进一步说明本发明,本发明未提及部分均为现有技术。 [0054] The following examples further illustrate embodiments in conjunction with the present invention, which are not mentioned in the prior art section.

[0055] 实施例1 [0055] Example 1

[0056] 合成化合物2 [0056] Synthesis of Compound 2

Figure CN107434780AD00121

[0058] 将50g化合物1(4-甲基苯乙酸)溶入200毫升四氯化碳中,加热至回流,加热状态下分批加入NBS(N-溴代丁二酰亚胺)(62g,0.35mol),加完后继续保持回流状态持续3小时,有大量固体析出来,TLC显示原料反应完全,将反应液冷却至室温,搅拌状态下倒入500毫升冰水中,继续搅拌20分钟,过滤,滤饼用水洗涤3次(每次300毫升),得到白色固体,将白色固体于50°C烘干10小时得到51g化合物2(4-溴甲基苯乙酸),化合物2不需继续纯化直接进行下一步反应。 [0058] 50g of compound 1 (4-methyl-phenylacetic acid) was dissolved in 200 ml of carbon tetrachloride was heated to reflux under heating was added portionwise NBS (N- bromosuccinimide) (62g, 0.35 mol), was added to maintain reflux after 3 hours, salted out with a large amount of solid, TLC showed starting material the reaction was complete, the reaction was cooled to room temperature, stirred state was poured into 500 ml of ice water, stirring was continued for 20 minutes, filtered , filter cake was washed with water 3 times (300 ml) to give a white solid, 51g of compound 2 as a white solid was obtained (4-bromo-phenylacetic acid) drying at 50 ° C for 10 hours to continue without purification compound 2 the next step reaction.

[0059] 合成化合物3 [0059] Synthesis of Compound 3

Figure CN107434780AD00122

[0061 ]将化合物2(50g)加入200毫升水中,搅拌加热至回流并保持2小时,反应变澄清, 然后冷却至室温,冰浴降温至2度左右,析出白色固体,过滤,滤饼用水洗涤2次得到白色固体,将白色固体于50 °C烘干10小时得到约33克化合物3。 [0061] Compound 2 (50g) was added 200 ml of water, stirred and heated to reflux for 2 hours, the reaction became clear, then cooled to room temperature, the ice bath was cooled to about 2 °, the precipitated white solid was filtered, the filter cake was washed with water twice to give a white solid, the white solid was 10 hours to obtain about 33 g of compound 3 in 50 ° C dry.

[0062]合成化合物4 [0062] Synthesis of Compound 4

Figure CN107434780AD00123

[0064] 将化合物3(30g)以及咪唑(18.5g)溶入300毫升DMF中,冰浴降温至0度,分批加入TBSCl (32.65g),自然升温至室温并搅拌过夜,TLC显示原料完全消失,冰浴降温至0°C左右, 用饱和氯化铵水溶液淬灭反应,并用IM稀盐酸调节pH值至3〜4,升温至室温搅拌半小时,用甲基叔丁基醚萃取3次(每次200毫升),合并有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤旋干得到粗品化合物4(46g),该粗品不需进一步纯化直接用于下一步反应。 [0064] Compound 3 (30g) and imidazole (18.5 g of) dissolved in 300 ml of DMF, the ice bath was cooled to 0 degrees, was added TBSCl (32.65g), naturally warmed to room temperature and stirred overnight, TLC showed starting material was completely disappears, the ice bath was cooled to about 0 ° C, with a reaction was quenched with saturated aqueous ammonium chloride, and adjusted to pH 3 to 4 with IM dilute hydrochloric acid, warmed to room temperature and stirred for half an hour, and extracted with methyl tert-butyl ether three times (200 ml), washed with saturated brine and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and rotary-dried to give crude compound 4 (46g), the crude product without further purification was used directly in the next reaction.

[0065] 合成化合物5(手性配体) [0065] Synthesis of Compound 5 (chiral ligand)

Figure CN107434780AD00124

[0067] 将化合物4(40g,142.64mmol)溶入无水四氢呋喃(500毫升)中,干冰丙酮降温至-10度,缓慢滴加草酰氯(11.Og),保持滴加温度不高于-10度,制备得到酰氯;同时在另外一个三口瓶中将21.16g(R)-4-苯基-2-噁唑烷酮加入500毫升无水四氢呋喃中,氮气置换,用干冰丙酮降温至-78度,缓慢滴加正丁基锂(2.5M,60ml)并保持温度在-78度,滴加完成后继续在-78度下搅拌1小时,然后通过恒压漏斗慢慢滴加前面制备的酰氯,保持滴加温度在-78 度,滴加完成后继续保持-78度反应2小时,然后自然升温至室温搅拌过夜。 [0067] Compound 4 (40g, 142.64mmol) was dissolved in dry tetrahydrofuran (500 ml), cooled to -10 degrees dry ice-acetone, was slowly added dropwise oxalyl chloride (11.Og), was added dropwise maintaining a temperature of not higher than - 10 degrees, the acid chloride prepared; while the other three-neck flask 21.16g (R) -4- phenyl-2-oxazolidinone in 500 ml of anhydrous tetrahydrofuran, purged with nitrogen, cooled to -78 with a dry ice acetone degrees, was slowly added dropwise n-butyllithium (2.5M, 60ml) and maintaining the temperature, after completion of the dropwise addition stirring was continued at -78 ° -78 ° for 1 hour then slowly added dropwise the previously prepared acid chloride by a constant pressure funnel , maintaining the temperature at -78 ° was added dropwise, after the completion of the dropwise addition of the reaction to maintain -78 for 2 hours and then allowed to warm to rt naturally and stirred overnight. 用饱和氯化铵水溶液淬灭反应,旋蒸除去四氢呋喃溶剂,残留物用乙酸乙酯萃取3次(每次300ml ),合并有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤旋干得到粗品化合物5,过柱纯化得到纯品化合物5(40.5g),收率73.39%。 Quenched with saturated aqueous ammonium chloride the reaction, the solvent was removed spin tetrahydrofuran was evaporated, the residue was extracted 3 times (300ml) with ethyl acetate, washed with saturated brine and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and rotary-dried to give The crude compound 5, was purified by column to give pure compound 5 (40.5 g of), a yield of 73.39%.

[0068]合成化合物6 [0068] Synthesis of Compound 6

Figure CN107434780AD00131

[0070] 将纯品化合物5(40g,94mmol)溶入无水四氢呋喃(400ml)中,氮气置换,干冰丙酮降温至-78度,缓慢滴加六甲基二硅胺钠的四氢呋喃溶液(112.Smmol,六甲基二硅胺钠的浓度为2mol/L),滴加完成后体系于-78度下搅拌1小时;化合物13(108mmol)溶于400毫升无水四氢呋喃(THF)中,通过恒压漏斗慢慢滴加前述体系中,控制滴加温度低于-70度,滴加结束后反应保持在-78度下搅拌3小时,自然升温至室温并搅拌过夜。 [0070] The pure compound 5 (40g, 94mmol) dissolved in dry tetrahydrofuran (400ml), purged with nitrogen, dry ice-acetone cooled to -78 °, was slowly added dropwise a tetrahydrofuran solution of sodium hexamethyldisilazide amine (112. Smmol, the concentration of sodium hexamethyldisilazane amines 2mol / L), after the completion of the dropwise addition was stirred 1 hour at -78 degrees; compound 13 (108mmol) was dissolved in 400 ml of dry tetrahydrofuran (THF) by the constant the system pressure was slowly dropped in the funnel, added dropwise to control the temperature below -70 ° C. after completion of the dropwise addition the reaction was kept stirring at -78 ° for 3 hours and warm naturally to room temperature and stirred overnight. TLC显示原料反应完全,用饱和氯化铵水溶液500毫升淬灭反应,旋蒸除去溶剂四氢呋喃,残留物用乙酸乙酯萃取3次(每次200毫升),合并有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤旋干得到粗品化合物6,过柱纯化得到纯品化合物6 (43g),收率(78.24%)。 TLC showed completion of the reaction starting material, reaction was quenched with 500 ml saturated aqueous ammonium chloride quench, tetrahydrofuran solvent was removed by rotary evaporation, the residue was extracted three times with ethyl acetate (200 ml), washed with saturated brine and the organic phases were combined, no over anhydrous sodium sulfate, filtered and rotary-dried to give the crude compound 6 was purified by column to give pure compound 6 (43g), yield (78.24%).

[0071 ]合成化合物7 [0071] Synthesis of Compound 7

Figure CN107434780AD00132

[0073] 将纯品化合物6(29.2g,0.05mol)加入300ml四氢呋喃和IOOml水中,冰水冷却反应体系至〇°C,然后加入氢氧化锂(6.3g,0.15mol),于0°C搅拌3小时。 [0073] Pure compound 6 (29.2g, 0.05mol) was added IOOml 300ml of tetrahydrofuran and water, ice water, the reaction was cooled to square ° C, followed by addition of lithium hydroxide (6.3g, 0.15mol), stirred the 0 ° C 3 hours. LC-MS监控反应至化合物6消失,减压蒸出有机溶剂有大量白色固体析出,过滤,室温下将滤液用IN的盐酸水溶液调pH至3-4,乙酸乙酯(IOOml)萃取四次,硫酸钠干燥,减压蒸干得白色泡沫状固体20. lg,未进一步纯化,直接用于下一步,纯度94.5%。 LC-MS to monitor the reaction to the disappearance of the compound 6, the organic solvent was distilled off under reduced pressure with a large amount of white solid was precipitated, filtered, and the filtrate was extracted four times at room temperature with aqueous hydrochloric acid adjusted to pH IN 3-4, ethyl acetate (IOOml), over sodium sulfate, and evaporated to dryness under reduced pressure to give a white foamy solid 20. lg, without further purification, was used directly in the next step, a purity of 94.5%.

[0074] 合成化合物7A [0074] Synthesis of Compound 7A

Figure CN107434780AD00133

[0076] 将化合物7(22 · 5g,0 · 05mol),H0BT(1-羟基苯并三唑)(6 · 75g,0 · 05mol)和三乙胺(25ml)加入干燥二氯甲烷(300ml),氮气保护,降温至(TC,然后向反应液中加入EDCI (22.5g,0.05mo 1),搅拌一段时间,反应液变澄清,缓慢升温至室温,反应过夜。将反应液减压蒸干至无溶剂,向残余物中加入200ml冰水,用冰冷过的盐酸水溶液调pH至2-3,EA萃取、 过柱纯化(二氯甲烷:甲醇=20 :1-10:1)得到化合物7A( 18.65g)白色泡沫状固体,收率85% ;LC-MS(Ml)438〇 [0076] Compound 7 (22 · 5g, 0 · 05mol), H0BT (1- hydroxybenzotriazole) (6 · 75g, 0 · 05mol) and triethylamine (25ml) was added dry dichloromethane (300ml) nitrogen, the temperature was lowered to (the TC, then the reaction solution was added EDCI (22.5g, 0.05mo 1), stirred for a period of time, the reaction solution became clear, slowly warmed to room temperature overnight. the reaction mixture was evaporated to dryness under reduced pressure to solvent-free, 200ml of ice water was added to the residue, treated with ice-cold aqueous hydrochloric acid to adjust pH to 2-3, EA and extracted, purified by column (dichloromethane: methanol = 20: 1-10: 1) to give compound 7A ( 18.65 g) as a white foamy solid, yield 85%; LC-MS (Ml) 438〇

[0077] 合成化合物8 [0077] Synthesis of Compound 8

Figure CN107434780AD00141

[0079] 在室温下将化合物7A( 10 · 9g,25mmol),6-氨基异喹啉(4 · 32g,30mmol)和EDCI (6 · 68g,35mmol)加入吡啶(100ml)中,氮气保护,然后加入DMAP(4-二甲氨基吡啶)(4 · 2g, 35mmol),反应过夜,TLC(DCM:MA = 20:1)监控反应至原料化合物7A消失,减压蒸干,3摩尔的醋酸水溶液调节到卩!1 = 4-5,001(1001111*4)萃取,合并过柱得到化合物8(11.028),收率78% ;LC-MS(M+1)566,纯度:97.4%。 [0079] The compound obtained in nitrogen atmosphere at room 7A (10 · 9g, 25mmol), 6- amino-isoquinoline (4 · 32g, 30mmol), and EDCI (6 · 68g, 35mmol) was added pyridine (100ml), then was added DMAP (4- dimethylaminopyridine) (4 · 2g, 35mmol), allowed to react overnight, TLC (DCM: MA = 20: 1) to monitor the reaction to the disappearance of the starting compound 7A, evaporated to dryness under reduced pressure, aqueous acetic acid adjusted to 3 molar ! = 1 to 4-5,001 Jie (1001111 * 4). the combined by column to give compound 8 (11.028), yield 78%; LC-MS (M + 1) 566, purity: 97.4%.

[0080] 合成化合物9 [0080] Synthesis of Compound 9

Figure CN107434780AD00142

[0082] 将化合物8(11.02g,19.5mmol)用乙醇(IOOml)溶解,向其中加入水合肼(85%, 9.75g,195mmol),加热至回流,约2小时候后有大量白色固体生成,然后继续反应3小时,7令却至5度,过滤,滤饼用冷乙醇洗涤,减压蒸干,用油栗减压至无溶剂,得到化合物9(11.4g), 直接用于下一步。 [0082] The compound 8 (11.02g, 19.5mmol) with ethanol (IOOml) was dissolved, and thereto was added hydrazine hydrate (85%, 9.75g, 195mmol), heated to reflux, with a large amount of white solid formed after about 2 child, then reaction was continued for 3 hours, cooled to 5 degrees so that 7, the filter cake was washed with cold ethanol, evaporated to dryness under reduced pressure until solvent-free oil Li, to give compound 9 (11.4g), was used directly in the next step.

[0083] 合成化合物10 [0083] Synthesis of Compound 10

Figure CN107434780AD00151

[0085] 将上步获得的化合物9 (11.4g,19.5mmo I)溶解在IOOml二氯甲烷中,然后向其中加入三乙胺(l〇ml),缓慢滴加(B0C)20(二碳酸二叔丁酯)(6七,0.29111111〇1)有大量气体放出, TLC(乙酸乙酯)监控反应至化合物9消失,减压蒸干,柱层析(EA:PE = 1:1)获得白色固体产物(9.49g),即为化合物10,收率:90 %。 [0085] The compound obtained in the above Step 9 (11.4g, 19.5mmo I) IOOml was dissolved in methylene chloride, to which was then added triethylamine (l〇ml), was slowly added dropwise (B0C) 20 (di tert-butyl) (6 VII 0.29111111〇1) a large number of gas evolution, TLC (ethyl acetate) monitoring the disappearance of the reaction to compound 9, and evaporated to dryness under reduced pressure, column chromatography (EA: PE = 1: 1) to give a white solid The product (9.49g), is the compound 10, yield: 90%.

[0086] 合成化合物11 [0086] Synthesis of Compound 11

Figure CN107434780AD00152

[0088] 将上步获得的化合物10(8g,15mmol)加入100ml THF(四氢呋喃)中,然后向其中加入四丁基氟化氨(7.83g,30mmol),搅拌过夜,TLC(EA)检测反应无化合物10,减压蒸干,残余物加入200ml水,搅拌30min,静止一段时间,倒去水,将黄褐色油状物溶于EA中硫酸钠干燥, 移除有机溶剂得到化合物11 (7.86g),为进一步处理,直接用于下一步。 [0088] The compound obtained in the above Step 10 (8g, 15mmol) was added 100ml THF (tetrahydrofuran), and then thereto was added tetrabutyl ammonium fluoride (7.83g, 30mmol), stirred overnight, TLC (EA) without detection reaction compound 10, evaporated to dryness, the residue was added 200ml of water, stirred for 30min, a period of inactivity, the water decanted, the tan oil was dissolved in EA and dried over sodium sulfate, the organic solvent is removed to give compound 11 (7.86g), for further processing, it was used directly in the next step.

[0089] 合成化合物12 [0089] Synthesis of Compound 12

Figure CN107434780AD00153

[0091] 将2,4-二甲基苯甲酸(1.5g,IOmmol)和催化量的DMF加于甲苯中,冷却至2-5°C,滴加草酰氯(I.64g,13_〇1),滴加完后升温到室温,搅拌过夜,在此过程中固体逐渐溶解得一澄清液,减压蒸干得一黄色油状物,用二氯甲烷(IOml)溶解得到二氯甲烷的酰氯溶液; [0091] The 2,4-dimethyl benzoic acid (1.5g, IOmmol) and a catalytic amount of DMF was added to the toluene and cooled to 2-5 ° C, was added dropwise oxalyl chloride (I.64g, 13_〇1 ), warmed to room temperature after dropwise, stirred overnight, during which a solid gradually dissolved to give a clear solution, evaporated to dryness under reduced pressure to give a yellow oil with dichloromethane (IOml) was dissolved in dichloromethane to give the acid chloride ;

[0092] 将化合物11 (3.2g,7.7mmo 1)和三乙胺(2ml)加入20ml二氯甲烷中,氮气保护,将上述制备得到的二氯甲烷的酰氯溶液在0-5 °C下滴入,加完后搅拌,反应过夜;TLC(二氯甲烷: 甲醇= 20:1)监控反应,反应完毕,减压蒸干,然后用饱和碳酸钠溶液搅拌,过滤,滤饼用水洗涤3次,烘干得到3.9g白色固体,即为化合物12;纯度:99. 1%,光学纯度:100% (CHIRALPAK AS-H,0.46cm IDX15cm L,Me0H+0.1DEA)/C02 = 20/80(V/V,2.0ml/min),R 型,Rt = 3 · 253min; S型Rt = 4.3min)。 [0092] Compound 11 (3.2g, 7.7mmo 1) and triethylamine (2ml) were added 20ml of dichloromethane, nitrogen, the above prepared acid chloride solution in dichloromethane dropwise at 0-5 ° C the increases after mixing, overnight; TLC (dichloromethane: methanol = 20: 1) to monitor the reaction, completion of the reaction, evaporated to dryness under reduced pressure, and then stirred with saturated sodium carbonate solution, filtered, the filter cake was washed with water 3 times, dried to give 3.9g white solid, i.e. compound 12; purity: 991%, optical purity: 100% (CHIRALPAK AS-H, 0.46cm IDX15cm L, Me0H + 0.1DEA) / C02 = 20/80 (V / V, 2.0ml / min), R-type, Rt = 3 · 253min; S type Rt = 4.3min).

[0093] 将化合物12(3.9g)加入DCM中,搅拌得澄清液,然后向其中滴加I,4_二氧六环的氯化氢溶液15ml(浓度为4mol/L,4mol HCl气体溶于IL二氧六环中),然后在室温下搅拌4小时,减压旋蒸、过滤得3.65g白色固体产物,经HNMR检测所得物质即为AR-13324盐酸盐,其IHNMR谱图参见图1所示,MS,纯度,99.4%,lHNMR(400MHz,DMS0,300)S(Ppm)c3Il .773(s, 1H),9.702(s,lH),8.740(d,lH),8.560(d,1H),8.469(d,1H),8.360(d,1H),8.280(s,3H), 8.158(dd,lH),7.777(d,lH),7.577(d,2H),7.496(d,2H),7.134(s,lH),7.111(d,lH), 5.281(s,2H),4.504(q,lH),3.609(q,lH),3.139(q,lH),2.483(s,3H),2.302(s,3H)。 [0093] Compound 12 (3.9g) in DCM was added, with stirring to obtain clear solution, was then added dropwise I, a solution of hydrogen chloride in dioxane 15ml 4_ (concentration 4mol / L, 4mol HCl gas dissolved in two IL oxygen six ring), and then stirred for 4 hours at room temperature, rotary evaporated under reduced pressure, and filtered to give 3.65g product as a white solid, was obtained HNMR detectable substance is the AR-13324 hydrochloride, which IHNMR spectrum Referring to FIG. 1 , MS, purity, 99.4%, lHNMR (400MHz, DMS0,300) S (Ppm) c3Il .773 (s, 1H), 9.702 (s, lH), 8.740 (d, lH), 8.560 (d, 1H), 8.469 (d, 1H), 8.360 (d, 1H), 8.280 (s, 3H), 8.158 (dd, lH), 7.777 (d, lH), 7.577 (d, 2H), 7.496 (d, 2H), 7.134 (s, lH), 7.111 (d, lH), 5.281 (s, 2H), 4.504 (q, lH), 3.609 (q, lH), 3.139 (q, lH), 2.483 (s, 3H), 2.302 ( s, 3H).

[0094] AR-13324盐酸盐的结构式如下所述: [0094] structural formula AR-13324 hydrochloride as follows:

Figure CN107434780AD00161

[0096] 实施例2 [0096] Example 2

[0097] 该实施例中,除了对化合物12的处理步骤不一样外,其余与实施例1相同。 [0097] In this embodiment, the same processing steps except that Compound 12, the other the same as in Example 1.

[0098] 对化合物12的处理步骤如下:将化合物12 (3.9g)溶于40ml二氯甲烷中,然后滴加甲磺酸(2g,21.6mmol),在室温下搅拌过夜,减压旋蒸,向其中加入IOOml乙醚,搅拌,产生大量白色固体,过滤,烘干得到白色固体(4.54g),收率,97.8 %,纯度98.2 %,经IHNMR检测所得物质即为AR-13324甲磺酸盐。 [0098] Compound 12 processing steps are as follows: The compound is dissolved in 12 (3.9g) 40ml of dichloromethane, followed by dropwise addition of methanesulfonic acid (2g, 21.6mmol), stirred at room temperature overnight, rotary evaporated under reduced pressure, IOOml diethyl ether was added thereto, followed by stirring, a large amount of white solid was filtered, dried to give a white solid (4.54 g of), yield 97.8%, purity 98.2%, the resulting substance was detected IHNMR AR-13324 is the mesylate salt.

[0099] 实施例3 [0099] Example 3

[0100] 该实施例中,除了化合物5的合成步骤不一样外,其余与实施例1相同。 [0100] In this embodiment, the step of synthesis of Compound 5 except that not the same, the other the same as in Example 1.

[0101] 合成化合物5A(手性配体) [0101] Synthesis of Compound 5A (chiral ligand)

Figure CN107434780AD00162

[0103] 化合物4(50g,178.3mmol)溶入无水四氢呋喃(500毫升)中,干冰丙酮降温至-10 度,缓慢滴加草酰氯(13g),保持滴加温度不高于-10度,得到酰氯;同时在另外一个三口瓶中将28.7g(R)-4-苄基-2-噁唑烷酮加入500毫升无水四氢呋喃中,氮气置换,用干冰丙酮降温至-78度,缓慢滴加7.2ml正丁基锂溶液(浓度为2.5mol/L)并保持温度在-78度,滴加完成后继续在-78度下搅拌1小时,将前面制备的酰氯通过恒压漏斗慢慢滴加到该三口瓶中,保持滴加温度在-78度,滴加完成后反应继续保持-78度2小时,然后自然升温至室温搅拌过夜。 [0103] Compound 4 (50g, 178.3mmol) dissolved in dry tetrahydrofuran (500 ml), cooled to -10 degrees dry ice-acetone, was slowly added dropwise oxalyl chloride (13g), was added dropwise maintaining the temperature not higher than -10 degrees, acid chloride; while the other three-neck flask 28.7g (R) -4- benzyl-2-oxazolidinone in 500 ml of anhydrous tetrahydrofuran, purged with nitrogen, cooled to -78 ° with a dry ice-acetone, was slowly added dropwise add 7.2ml of n-butyllithium solution (concentration 2.5mol / L) and maintaining the temperature, after completion of the dropwise addition stirring was continued for 1 hour at -78 ° -78 °, the previously prepared acid chloride was slowly dropwise by a constant pressure funnel the three-neck flask was added, dropwise maintaining the temperature at -78 °. after the addition reaction was completed to maintain -78 degrees for 2 hours and then allowed to warm to rt naturally and stirred overnight. 用饱和氯化铵水溶液淬灭反应,旋蒸除去四氢呋喃溶剂,残留物用乙酸乙酯萃取3次(每次300ml),合并有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤旋干得到粗品化合物5A, 过柱纯化得到纯品5A(50g),收率70.13%。 Quenched with saturated aqueous ammonium chloride the reaction, the solvent was removed spin tetrahydrofuran was evaporated, the residue was extracted 3 times (300ml) with ethyl acetate, washed with saturated brine and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and rotary-dried to give The crude compound 5A, purified by column to give pure 5A (50g), a yield of 70.13%.

[0104]实施例3的合成路线如下: [0104] Example of Scheme 3 as follows:

Figure CN107434780AD00171

Claims (10)

  1. 1. 一种AR-13324的制备方法,其特征在于利用手性配体手性诱导合成AR-13324,手性配体的结构式如式5所示: 1. A process for producing AR-13324, which is characterized in that using a chiral ligand chiral AR-13324 induces the synthesis, structural formula of chiral ligands as shown in Formula 5:
    Figure CN107434780AC00021
    X为OTBS、OTIPS,Y为?11、811、卜1311、4-硝基苯基或4-甲氧基苯基,八为氧或硫。 X is OTBS, OTIPS, Y is? 11,811, Bu 1311,4- nitrophenyl or 4-methoxyphenyl, eight is oxygen or sulfur.
  2. 2. 根据权利要求1所述的制备方法,其特征在于手性配体的合成步骤如下:(1)通过TBSCl或TIPSCl对4-(羟基甲基)苯乙酸中的羟基进行保护,得到粗品化合物4; 2. The production method according to claim 1, wherein the step of synthesizing a chiral ligand as follows: (1) Protection of 4- (hydroxymethyl) phenylacetic acid or the hydroxyl group by TBSCl TIPSCl, to give crude compound 4;
    Figure CN107434780AC00022
    X为OTBS、OTIPS, (2)将化合物4、不对称合成手性助剂溶于有机溶剂中,加入草酰氯,干冰丙酮降温,在 X is OTBS, OTIPS, (2) Compound 4, asymmetric synthesis of the chiral auxiliary in an organic solvent, was added oxalyl chloride, dry ice-acetone cooling, the
    Figure CN107434780AC00023
    催化剂作用下反应得到手性配体,手性配体的结构式如式5所示: X为> OTBS、OTIPS,Y为?11、811、丨-1311、4-硝基苯基或4-甲氧基苯基4为氧或硫。 Reaction catalyst to give chiral ligands, chiral ligands of Formula 5 as shown in Formula: X is> OTBS, OTIPS, Y is 11,811, Shu -1311,4- or 4-nitrophenyl? 4 is a phenyl group having an oxygen or sulfur.
  3. 3. 根据权利要求1或2所述的制备方法,其特征在于利用手性配体手性诱导合成AR-13324 包括如下步骤: (1) 通过TBSCl或TI PSCl对4-(羟基甲基)苯乙酸中的羟基进行保护,得到粗品化合物4; The production method of claim 1 or claim 2, characterized in that using a chiral ligand induces the synthesis of chiral AR-13324 comprising the steps of: (1) by TBSCl or TI PSCl of 4- (hydroxymethyl) benzene protected hydroxy acetic acid, to give crude compound 4;
    Figure CN107434780AC00024
    X为OTBS、OTIPS, (2) 将化合物4、不对称合成手性助剂溶于有机溶剂中,加入草酰氯,干冰丙酮降温,在 X is OTBS, OTIPS, (2) Compound 4, asymmetric synthesis of the chiral auxiliary in an organic solvent, was added oxalyl chloride, dry ice-acetone cooling, the
    Figure CN107434780AC00025
    催化剂作用下反应得到手性配体,手性配体的结构式如式5所示: X为,+ OTBS、OTIPS,Y为?11、811、丨-1311、4-硝基苯基或4-甲氧基苯基4为氧或硫; (3) 将化合物5、六甲基二硅胺钠、化合物13溶于有机溶剂中,干冰丙酮降温,搅拌反应, 然后升温至室温并搅拌过夜,得到粗品化合物6,过柱纯化得到纯品化合物6; Reaction catalyst to give chiral ligands, chiral ligands of Formula 5 as shown in Formula: X is, + OTBS, OTIPS, Y is 11,811, or 4-nitrophenyl Shu -1311,4-? methoxyphenyl 4 is oxygen or sulfur; (3) the compound 5, sodium hexamethyldisilazane amine, compound 13 is dissolved in an organic solvent, a dry ice acetone cooling, the reaction was stirred, then warmed to room temperature and stirred overnight to give The crude compound 6 was purified by column to give pure compound 6;
    Figure CN107434780AC00026
    X为OTBS、OTIPS,Y为?11、811、卜1311、4-硝基苯基或4-甲氧基苯基,八 X is OTBS, OTIPS, Y is? 11,811, Bu 1311,4- nitrophenyl or 4-methoxyphenyl, eight
    Figure CN107434780AC00031
    , 为氧或硫; (4) 将化合物6加入有机溶剂和水中,冰水冷却,然后加入氢氧化锂,搅拌反应,调节PH 值,减压蒸出有机溶剂、然后过滤,滤液经萃取、干燥、减压蒸干得到化合物7; , Is oxygen or sulfur; (4) Compound 6 is added an organic solvent and water, cooling with ice, followed by addition of lithium hydroxide, the reaction was stirred, PH adjustment values, the organic solvent was distilled off under reduced pressure, and then filtered, and the filtrate was extracted, dried , evaporated to dryness under reduced pressure to give compound 7;
    Figure CN107434780AC00032
    X为OTBS、OTIPS; (5) 将化合物7、1-羟基苯并三唑、三乙胺加入到干燥二氯甲烷中,氮气保护,降温,向反应液中加入EDCI,升温搅拌,然后将反应液减压蒸干至无溶剂,向残余物中加入冰水,调节pH,经萃取、纯化得到化合物7A; X is OTBS, OTIPS; (5) The compound 7,1- hydroxybenzotriazole, triethylamine were added to dry dichloromethane, nitrogen, cooling, EDCI was added to the reaction mixture was heated with stirring, then the reaction was evaporated to dryness under reduced pressure until no solvent, to the residue was added ice-water, the pH adjusted, by extraction, to give compound. 7A;
    Figure CN107434780AC00033
    X为OTBS、OTIPS; (6) 将化合物7A、6-氨基异喹啉和EDCI加入吡啶中,氮气保护,然后加入4-二甲氨基吡啶,反应过夜,反应完全后减压蒸干得到化合物8; X is OTBS, OTIPS; (6) Compound 7A, 6- aminoisoquinoline and EDCI was added pyridine nitrogen, followed by the addition of 4-dimethylaminopyridine, the reaction overnight, the reaction was complete and evaporated to dryness under reduced pressure to give Compound 8 ;
    Figure CN107434780AC00034
    X为OTBS、OTIPS; (7) 将化合物8溶于有机溶剂中,向其中加入水合肼,加热至回流,反应完成后冷却,过滤,得到化合物9; X is OTBS, OTIPS; (7) Compound 8 is dissolved in an organic solvent, to which was added hydrazine hydrate and heated to reflux, After the reaction was cooled and filtered to give compound 9;
    Figure CN107434780AC00041
    X为OTBS、OTIPS; (8) 引入叔丁氧羰基对化合物9中的氨基进行保护,得到化合物IO; X is OTBS, OTIPS; (8) introduced into the t-butoxycarbonyl group in compound 9 to protect the amino group, to give a compound of the IO;
    Figure CN107434780AC00042
    X为OTBS、OTIPS; (9) 将化合物10加入有机溶剂中,然后加入四丁基氟化氨进行反应,反应完成后减压蒸干,得到化合物11; X is OTBS, OTIPS; (9) Compound 10 is added an organic solvent, followed by addition of tetrabutylammonium fluoride ammonia reaction, after the completion of the reaction to dryness under reduced pressure, to give compound 11;
    Figure CN107434780AC00043
    (10) 将2,4_二甲基苯甲酸和二甲基甲酰胺加于甲苯中,冷却,加入草酰氯,升温反应、 反应完成后减压蒸干得到黄色油状物、将其溶于二氯甲烷中得到二氯甲烷的酰氯溶液; 将化合物11、三乙胺、加入到二氯甲烷中,氮气保护,然后加入二氯甲烷的酰氯溶液,反应完成后减压蒸干,然后经洗涤、过滤后得到化合物12; (10) The 2,4_ dimethyl benzoic acid and dimethyl formamide was added to the toluene and cooled, was added oxalyl chloride, heating the reaction, after the completion of the reaction evaporated to dryness under reduced pressure to give a yellow oil, which was dissolved in two chloride to give acid chloride solution in dichloromethane; compound 11, triethylamine was added to the methylene chloride, a nitrogen atmosphere, followed by addition of the acid chloride in dichloromethane, evaporated to dryness under reduced pressure after the completion of the reaction, and then washed, after filtration to give compound 12;
    Figure CN107434780AC00044
    (11) 将化合物12溶于二氯甲烷中,然后加入甲磺酸或1,4_二氧六环的氯化氢溶液于室温下搅拌,减压旋蒸、过滤得到AR-13324甲磺酸盐或者盐酸盐; (11) Compound 12 was dissolved in dichloromethane, followed by addition of methanesulfonic acid or hydrogen chloride 1,4_-dioxane was stirred at room temperature, rotary evaporated under reduced pressure, filtered to give mesylate or AR-13324 Hydrochloride;
    Figure CN107434780AC00051
  4. 4. 根据权利要求3所述的制备方法,其特征在于步骤(2)中,将化合物4溶于无水四氢呋喃中,降温至-8〜-12°C,缓慢滴加草酰氯,保温,得到酰氯;同时另外将不对称合成手性助剂加入无水四氢呋喃中,用干冰丙酮降温至_78°C,加入正丁基锂,保温搅拌,然后加入酰氯继续反应1〜3小时,升温至室温搅拌过夜;终止反应,除去四氢呋喃溶剂,残留物经萃取、洗涤、干燥得到粗品化合物5,纯化后得到纯品化合物5;加入的化合物4与不对称合成手性助剂的摩尔比为0.8〜1.3:1,化合物4与草酰氯的摩尔比为1〜2:1。 4. The method of preparation according to claim 3, wherein the step (2), Compound 4 was dissolved in anhydrous tetrahydrofuran was cooled to -8~-12 ° C, was slowly added dropwise oxalyl chloride, insulation, to give chloride; while additionally the asymmetric synthesis of the chiral auxiliary was added anhydrous tetrahydrofuran, cooled to _78 ° C with dry ice-acetone, was added n-butyl lithium, keep stirring, followed by addition of the acid chloride the reaction was continued 1 ~ 3 hours, warmed to room temperature was stirred overnight; termination of the reaction, tetrahydrofuran solvent was removed, the residue was extracted, washed, and dried to give crude compound 5, to give pure compound 5; compound 4 is added with a molar ratio of the asymmetric synthesis of the chiral auxiliary is 0.8~1.3 : 1, the molar ratio of the compound with oxalyl chloride is 4 ~ 2: 1.
  5. 5. 根据权利要求4所述的制备方法,其特征在于步骤(3)中,将化合物5溶入无水四氢呋喃中,干冰丙酮降温降温至_78°C度,加入六甲基二硅胺钠保温反应0.5〜1.5小时;将化合物13溶于无水四氢呋喃后加入前述反应体系中,保温反应2〜4小时,自然升温至室温并搅拌过夜,反应完全后除去溶剂四氢呋喃,残留物经萃取、洗涤、干燥得到粗品化合物6,纯化后得到纯品化合物6;加入的化合物5与六甲基二硅胺钠的摩尔比为16〜17:20,加入的化合物5与化合物13的摩尔比为17〜18:20。 The production method as claimed in claim 4, wherein the step (3), the compound 5 dissolved in dry tetrahydrofuran, cooled to dry ice-acetone cooling of _78 ° C, was added sodium hexamethyldisilazide amine the reaction 0.5~1.5 hours incubation; compound 13 was dissolved in the reaction system was added anhydrous tetrahydrofuran, reaction was incubated 2 ~ 4 hours, allowed to warm to rt naturally and stirred overnight, the reaction was completed the solvent was removed tetrahydrofuran, the residue was extracted, washed and dried to give the crude compound 6, compound 6 to give the pure product after purification; molar ratio of the added compound 5 with sodium hexamethyldisilazane amines 16~17: 20, compound 5 is added 13 molar ratio of the compound is 17~ 18:20.
  6. 6. 根据权利要求5所述的制备方法,其特征在于步骤(4)中,将化合物6加入有机溶剂和水中,冰水冷却至(TC,然后加入氢氧化锂搅拌反应2.5〜3.5小时,减压蒸出有机溶剂、然后过滤,滤液经萃取、干燥、减压蒸干得到化合物7;加入的化合物6与氢氧化锂的摩尔比为0.5 〜1.5:3,有机溶剂与水的体积比为1〜3:1。 6. The production method according to claim 5, wherein the step (4), the compound 6 is added an organic solvent and water, cooled to ice-water (the TC, lithium hydroxide was then added to the stirred reaction 2.5~3.5 hours, Save the organic solvent was distilled off pressure, then filtered, and the filtrate was extracted, dried, and evaporated to dryness under reduced pressure to give compound 7; was added compound 6 and the molar ratio of lithium hydroxide is 0.5 ~ 1.5: 3, volume ratio of organic solvent to water is 1 ~ 3: 1.
  7. 7. 根据权利要求6所述的制备方法,其特征在于步骤(5)中,将化合物7、1-羟基苯并三唑、三乙胺加入到干燥二氯甲烷中,氮气保护,降温至(TC,向反应液中加入EDCI,升温至室温搅拌,反应过夜,然后将反应液减压蒸干至无溶剂,向残余物中加入冰水,调节PH至3-4, 经萃取、纯化得到化合物7A;加入的化合物7与1 -羟基苯并三唑的摩尔比为0.8〜1.3 :1,加入的化合物7与EDCI的摩尔比为0.7〜1:1,化合物7与三乙胺的摩尔比为0.2〜0.3:1。 The production method according to claim 6, wherein the step (5), the compound 7,1- hydroxybenzotriazole, triethylamine were added to dry dichloromethane in a nitrogen atmosphere, cooled to ( TC, the reaction mixture was added to EDCI, warmed to room temperature with stirring overnight, the reaction solution was then evaporated to dryness under reduced pressure until no solvent, to the residue was added ice-water, adjusted to PH 3-4, by extraction, to give compound . 7A; compound 7 was added l - hydroxybenzotriazole molar ratio of 0.8~1.3: 1, the molar ratio of compound 7 were added EDCI is 0.7~1: 1, the molar ratio of compound 7 as triethylamine 0.2~0.3: 1.
  8. 8. 根据权利要求7所述的制备方法,其特征在于步骤(7)中,冷却至4〜6°C,加入的化合物8与水合肼的摩尔比为0.05〜0.2:1。 8. The production method according to claim 7, wherein the step (7), cooled to 4~6 ° C, the molar ratio of the compound 8 with hydrazine hydrate was added to 0.05~0.2: 1.
  9. 9. 根据权利要求8所述的制备方法,其特征在于步骤(8)中,将化合物9溶于二氯甲烷中,然后加入三乙胺和二碳酸二叔丁酯进行反应,反应完成后减压蒸干,得到化合物10;加入的化合物9与三乙胺的摩尔比为0.06〜0.08:1,加入的化合物9与二碳酸二叔丁酯的摩尔比为66〜68:1。 9. A method of preparation according to claim 8, wherein the step (8), the compound 9 dissolved in methylene chloride, followed by addition of triethylamine and di-tert-butyl dicarbonate is reacted, after completion of the reaction Save pressure evaporated to dryness to give compound 10; compound 9 was added triethylamine molar ratio is 0.06~0.08: 1, compound 9 was added with di-tert-butyl ester molar ratio of 66~68: 1.
  10. 10. 根据权利要求9所述的制备方法,其特征在于步骤(10)中,将2,4_二甲基苯甲酸和二甲基甲酰胺溶于甲苯中,冷却至2-5 °C,加入草酰氯后升温到室温,搅拌过夜,减压蒸干得到黄色油状物、将其溶于二氯甲烷中得到二氯甲烷的酰氯溶液,加入的2,4_二甲基苯甲酸与草酰氯的摩尔比为9〜11:13; 将化合物11、三乙胺加入到二氯甲烷中,氮气保护,然后于0-5°C缓慢加入二氯甲烷的酰氯溶液进行反应,反应完成后减压蒸干,然后经洗涤、过滤后得到化合物12,加入的化合物11与加入的2,4-二甲基苯甲酸的摩尔比为0.7〜0.8:1。 10. The production method according to claim 9, wherein the step (10), the 2,4_ dimethyl benzoic acid and dimethyl formamide was dissolved in toluene and cooled to 2-5 ° C, after addition of oxalyl chloride was warmed to room temperature, stirred overnight, evaporated to dryness under reduced pressure to give a yellow oil, and the resulting acid chloride was dissolved in dichloromethane dichloromethane, the 2,4_-dimethylbenzoic acid with oxalyl chloride molar ratio of 9~11: 13; compound 11, triethylamine were added to methylene chloride, nitrogen, and then at 0-5 ° C was slowly added a solution of the acid chloride in methylene chloride is reacted, after completion of the reaction under reduced pressure evaporated to dryness, then washed and filtered to give compound 12, and the molar ratio of benzoic acid was added 11 2,4-dimethyl compound added is 0.7~0.8: 1.
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