CN116589367A - 一种盐酸达泊西汀的制备方法 - Google Patents
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- 229960005217 dapoxetine Drugs 0.000 title claims abstract description 28
- USRHYDPUVLEVMC-FQEVSTJZSA-N dapoxetine Chemical compound C1([C@H](CCOC=2C3=CC=CC=C3C=CC=2)N(C)C)=CC=CC=C1 USRHYDPUVLEVMC-FQEVSTJZSA-N 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- KJCVRFUGPWSIIH-UHFFFAOYSA-N 1-naphthol Chemical compound C1=CC=C2C(O)=CC=CC2=C1 KJCVRFUGPWSIIH-UHFFFAOYSA-N 0.000 claims abstract description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000007858 starting material Substances 0.000 claims abstract description 8
- 239000012359 Methanesulfonyl chloride Substances 0.000 claims abstract description 7
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims abstract description 7
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims abstract description 7
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims abstract description 7
- 230000009467 reduction Effects 0.000 claims abstract description 7
- KTJRGPZVSKWRTJ-UHFFFAOYSA-N 3-chloro-1-phenylpropan-1-one Chemical compound ClCCC(=O)C1=CC=CC=C1 KTJRGPZVSKWRTJ-UHFFFAOYSA-N 0.000 claims abstract description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 30
- 238000006243 chemical reaction Methods 0.000 claims description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 15
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 12
- KHYAFFAGZNCWPT-UHFFFAOYSA-N boron;n,n-diethylaniline Chemical compound [B].CCN(CC)C1=CC=CC=C1 KHYAFFAGZNCWPT-UHFFFAOYSA-N 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 11
- 239000007787 solid Substances 0.000 claims description 11
- 238000003756 stirring Methods 0.000 claims description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 9
- 239000003960 organic solvent Substances 0.000 claims description 8
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 6
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 239000012044 organic layer Substances 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 4
- 230000009471 action Effects 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- 239000002699 waste material Substances 0.000 abstract description 7
- 238000009776 industrial production Methods 0.000 abstract description 6
- XHFGWHUWQXTGAT-UHFFFAOYSA-N dimethylamine hydrochloride Natural products CNC(C)C XHFGWHUWQXTGAT-UHFFFAOYSA-N 0.000 abstract description 4
- IQDGSYLLQPDQDV-UHFFFAOYSA-N dimethylazanium;chloride Chemical compound Cl.CNC IQDGSYLLQPDQDV-UHFFFAOYSA-N 0.000 abstract description 4
- 238000011112 process operation Methods 0.000 abstract 1
- 238000001035 drying Methods 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 238000006722 reduction reaction Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 230000001376 precipitating effect Effects 0.000 description 3
- 238000011914 asymmetric synthesis Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 206010036596 premature ejaculation Diseases 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- 229940124834 selective serotonin reuptake inhibitor Drugs 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- APYGJPRINQKIQF-SECBINFHSA-N (1r)-1-(3-chlorophenyl)propan-1-ol Chemical compound CC[C@@H](O)C1=CC=CC(Cl)=C1 APYGJPRINQKIQF-SECBINFHSA-N 0.000 description 1
- VCNYPJMEQHTAHS-UHFFFAOYSA-N 1-(3-chlorophenyl)propan-2-one Chemical compound CC(=O)CC1=CC=CC(Cl)=C1 VCNYPJMEQHTAHS-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000012069 chiral reagent Substances 0.000 description 1
- UOALEFQKAOQICC-UHFFFAOYSA-N chloroborane Chemical compound ClB UOALEFQKAOQICC-UHFFFAOYSA-N 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229930013356 epothilone Natural products 0.000 description 1
- 150000003883 epothilone derivatives Chemical class 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 239000002910 solid waste Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/64—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of functional groups containing oxygen only in singly bound form
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- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02P20/00—Technologies relating to chemical industry
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Abstract
本发明涉及一种盐酸达泊西汀的制备方法,具体包括以下步骤:3‑氯苯丙酮和1‑萘酚缩合制备得到中间体M1,M1经手性还原制备得到中间体M2,M2经甲磺酰氯、二甲胺盐酸盐、氯化氢等反应得到盐酸达泊西汀。本发明所述的盐酸达泊西汀的制备方法,起始物料廉价易得,工艺过程操作简单、收率高、成本低、三废少,适合工业化生产要求。
Description
技术领域
本发明涉及一种盐酸达泊西汀的制备方法,属于医药技术领域。
背景技术
盐酸达泊西汀(Dapoxetine hydrochloride)化学名为(S)-(+)-(N,N-二甲胺基)-3-(萘基-1-氧基)-1-苯基丙烷盐酸盐,是一种选择性5-羟色胺再摄取抑制剂(SSRIs),2009年在欧洲上市,用于成年男子早泄的按需治疗,是世界上第一个被批准用于治疗早泄的口服药,与传统的SSRIs相比,盐酸达泊西汀半衰期短、副作用小,具有更好的安全性和耐受性。
盐酸达泊西汀分子结构中含有一个手性中心,文献报道的合成方法大概分为两类:化学拆分法和不对称合成法。
专利EP0288188公开制备得到达泊西汀外消旋体,再用酒石酸拆分得到S-达泊西汀。手性试剂拆分法理论收率只有50%,另外的R-达泊西汀只能作为副产物无法利用,造成了极大的浪费和三废污染。
文献(合成化学2010,18(5):647-649)报道3-氯苯丙酮在硼氢化钠、无水氯化亚锡与(S)-(-)-α,α-二苯基脯氨醇不对称还原体系下生成(R)-(+)-3-氯苯丙醇,再进行后续反应得到S-达泊西汀。但该路线手性还原试剂较贵,三废多,不适合工业化生产。
专利CN201710642881公开使用3-氯苯丙酮和1-萘酚缩合制备得到中间体4,经手性还原制备得到中间体5,再进行后续反应得到S-达泊西汀。该路线所用手性还原试剂(-)二异松蒎基氯硼烷价格昂贵,不适合工业化生产。
从提高原子利用率和环保角度考虑,不对称合成是手性药物制备的最佳途径,因此需要一种成本较低、产率高、产品质量好、三废少,适合工业化生产的盐酸达泊西汀手性制备方法。
发明内容
本发明针对上述问题,提供了一种盐酸达泊西汀的制备方法,产品总收率57.6%、产品纯度99.9%、三废少,适合工业化生产。本发明的技术方案如下:
一种盐酸达泊西汀的制备方法,包括以下步骤:
(1)起始物料3-氯苯丙酮(SM1)和1-萘酚(SM2)缩合制备得到中间体M1;
(2)中间体M1经手性还原制备得到中间体M2;手性还原试剂为(1S,2R)-(-)-1-氨基-2-茚醇和硼烷-N,N-二乙基苯胺的混合物;
(3)中间体M2以四氢呋喃为溶剂,在三乙胺、DMAP作用下与甲磺酰氯酯化、再与二甲胺缩合,最后与氯化氢成盐得到盐酸达泊西汀。
化学反应式如式一所示:
式一
进一步的,所述步骤(1)中的反应条件为氮气保护,60~70℃反应12h。
进一步的,所述步骤(2)中M1与(1S,2R)-(-)-1-氨基-2-茚醇的摩尔比为1:0.02~1:2,优选为1:0.1~1:0.5。
进一步的,所述步骤(2)中M1与硼烷-N,N-二乙基苯胺的摩尔比为1:0.2~1:2,优选为1:0.5~1:1。
进一步的,所述步骤(2)中各物质需要溶于有机溶剂中,所述有机溶剂选自四氢呋喃、2-甲基四氢呋喃或1,4-二氧六环中的一种或多种,优选为四氢呋喃。
更进一步的,所述步骤(2)的具体步骤为:
反应瓶中加入有机溶剂、(1S,2R)-(-)-1-氨基-2-茚醇,降温至-5~0℃搅拌,缓慢加入硼烷-N,N-二乙基苯胺,继续保温,获得溶液A;另将M1溶解于有机溶剂中,缓慢滴加至溶液A中,滴毕,室温反应;然后减压蒸干溶剂,加入乙酸乙酯50ml,用质量浓度为10%的硫酸洗涤,分液,有机层减压蒸干,得到白色固体,即中间体M2。
本发明与现有技术相比具有以下优点:
3-氯苯丙酮和1-萘酚缩合制备得到中间体M1,中间体M1经手性还原制备得到中间体M2,中间体M2在三乙胺、DMAP作用下与甲磺酰氯酯化、再与二甲胺缩合,最后与氯化氢成盐得到盐酸达泊西汀。其中,手性还原试剂采用(1S,2R)-(-)-1-氨基-2-茚醇和硼烷-N,N-二乙基苯胺,该试剂价格低廉,手性还原反应收率高(>92%),产品纯度高(>99%)。采用手性合成技术制备中间体M2,避免传统化学拆分工艺(理论收率50%,对映异构体只能作为固废),三废少,适合工业化生产要求。
附图说明
图1为实施例1获得的盐酸达泊西汀的HPLC图;
图2为实施例2获得的盐酸达泊西汀的HPLC图;
图3为实施例3获得的盐酸达泊西汀的HPLC图。
具体实施方式
下面结合具体实施例来进一步描述本发明,本发明的优点和特点将会随着描述而更为清楚。但实施例仅是范例性的,并不对本发明的范围构成任何限制。本领域技术人员应该理解的是,在不偏离本发明的精神和范围下可以对本发明技术方案的细节和形式进行修改或替换,但这些修改和替换均落入本发明的保护范围内。
实施例1:
1、中间体M1的制备
反应瓶中加入3-氯苯丙酮(SM1)(10g,0.059mol)、1-萘酚(SM2)(10g,0.069mol)、无水碳酸钾12.5g、DMF50ml,氮气保护,60~70℃反应12h。待反应完全,倒入水中,搅拌析固,抽滤,干燥,得红棕色固体M1 10.8g,收率66%。
2、中间体M2的制备
反应瓶中加入四氢呋喃20ml、(1S,2R)-(-)-1-氨基-2-茚醇(0.54g,0.0036mol),降温至-5~0℃搅拌1h,缓慢加入硼烷-N,N-二乙基苯胺(4.6g,0.029mol),继续保温1h;另将M1(10g,0.036mol)溶解于四氢呋喃30ml中,缓慢滴加至上述溶液中,滴毕,室温反应3h。减压蒸干溶剂,加入乙酸乙酯50ml,用10%的硫酸洗涤,分液,有机层减压蒸干,得到白色固体M2 9.3g,收率为92%,光学纯度(ee)99.3%。
3、盐酸达泊西汀的制备
反应瓶中加入M2(9g,0.032mol)、三乙胺(4.9g,0.048mol),DMAP(0.4g,0.0032mol)、四氢呋喃90ml,搅拌降温至0~5℃,缓慢滴加甲磺酰氯(7.3g,0.038mol),保持0~5℃反应1h。加入二甲胺盐酸盐(2.9g,0.035mol),35℃反应6h。减压蒸除溶剂,加水,乙酸乙酯提取(50ml×2),无水硫酸钠干燥,过滤。滤液降温至0~5℃,通入氯化氢气体至pH2~3,搅拌0.5h保持不变。继续搅拌1~2h,过滤,干燥,得白色固体盐酸达泊西汀9.4g,收率95%,纯度99.98%,高效液相色谱(HPLC)如图1所示。
实施例2
1、中间体M1的制备
反应瓶中加入3-氯苯丙酮(SM1)(10g,0.059mol)、1-萘酚(SM2)(10g,0.069mol)、无水碳酸钾15g、DMF50ml,氮气保护,60~70℃反应12h。待反应完全,倒入水中,搅拌析固,抽滤,干燥,得红棕色固体M1 10.9g,收率67%。
2、中间体M2的制备
反应瓶中加入四氢呋喃20ml、(1S,2R)-(-)-1-氨基-2-茚醇(1.08g,0.0072mol),降温至-5~0℃搅拌1h,缓慢加入硼烷-N,N-二乙基苯胺(5.7g,0.036mol),继续保温1h;另将M1(10g,0.036mol)溶解于四氢呋喃30ml中,缓慢滴加至上述溶液中,滴毕,室温反应3h。减压蒸干溶剂,加入乙酸乙酯50ml,用10%的硫酸洗涤,分液,有机层减压蒸干,得到白色固体M2 9.4g,收率为93%,光学纯度(ee)99.3%。
3、盐酸达泊西汀的制备
反应瓶中加入M2(9g,0.032mol)、三乙胺(4.9g,0.048mol),DMAP(0.4g,0.0032mol)、四氢呋喃90ml,搅拌降温至0~5℃,缓慢滴加甲磺酰氯(7.3g,0.038mol),保持0~5℃反应1h。加入二甲胺盐酸盐(3.1g,0.038mol),35℃反应6h。减压蒸除溶剂,加水,乙酸乙酯提取(50ml×2),无水硫酸钠干燥,过滤。滤液降温至0~5℃,通入氯化氢气体至pH2~3,搅拌0.5h保持不变。继续搅拌1~2h,过滤,干燥,得白色固体盐酸达泊西汀9.4g,收率95%,纯度99.95%,高效液相色谱(HPLC)如图2所示。
实施例3
1、中间体M1的制备
反应瓶中加入3-氯苯丙酮(SM1)(10g,0.059mol)、1-萘酚(SM2)(10g,0.069mol)、无水碳酸钾12.5g、DMF80ml,氮气保护,60~70℃反应12h。待反应完全,倒入水中,搅拌析固,抽滤,干燥,得红棕色固体M1 10.8g,收率66%。
2、中间体M2的制备
反应瓶中加入四氢呋喃20ml、(1S,2R)-(-)-1-氨基-2-茚醇(1.62g,0.0108mol),降温至-5~0℃搅拌1h,缓慢加入硼烷-N,N-二乙基苯胺(3.2g,0.02mol),继续保温1h;另将M1(10g,0.036mol)溶解于四氢呋喃30ml中,缓慢滴加至上述溶液中,滴毕,室温反应3h。减压蒸干溶剂,加入乙酸乙酯50ml,用10%的硫酸洗涤,分液,有机层减压蒸干,得到白色固体M2 9.4g,收率为93%,光学纯度(ee)99.3%。
3、盐酸达泊西汀的制备
反应瓶中加入M2(9g,0.032mol)、三乙胺(4.9g,0.048mol),DMAP(0.4g,0.0032mol)、四氢呋喃90ml,搅拌降温至0~5℃,缓慢滴加甲磺酰氯(7.3g,0.038mol),保持0~5℃反应1h。加入二甲胺盐酸盐(2.9g,0.035mol),35℃反应6h。减压蒸除溶剂,加水,乙酸乙酯提取(50ml×2),无水硫酸钠干燥,过滤。滤液降温至0~5℃,通入氯化氢气体至pH2~3,搅拌0.5h保持不变。继续搅拌1~2h,过滤,干燥,得白色固体盐酸达泊西汀9.4g,收率95%,纯度99.97%,高效液相色谱(HPLC)如图3所示。
Claims (9)
1.一种盐酸达泊西汀的制备方法,其特征在于,所述制备方法包括以下步骤:
(1)起始物料3-氯苯丙酮(SM1)和1-萘酚(SM2)缩合制备得到中间体M1;
(2)中间体M1经手性还原制备得到中间体M2;手性还原试剂为(1S,2R)-(-)-1-氨基-2-茚醇和硼烷-N,N-二乙基苯胺的混合物;
(3)中间体M2以四氢呋喃为溶剂,在三乙胺、DMAP作用下与甲磺酰氯酯化、再与二甲胺缩合,最后与氯化氢成盐得到盐酸达泊西汀;化学反应式如式一所示:
2.根据权利要求1所述的制备方法,其特征在于,所述步骤(1)中的反应条件为氮气保护,60~70℃反应12h。
3.根据权利要求1所述的制备方法,其特征在于,所述步骤(2)中M1与(1S,2R)-(-)-1-氨基-2-茚醇的摩尔比为1:0.02~1:2。
4.根据权利要求3所述的制备方法,其特征在于,所述步骤(2)中M1与(1S,2R)-(-)-1-氨基-2-茚醇的摩尔比为1:0.1~1:0.5。
5.根据权利要求1所述的制备方法,其特征在于,所述步骤(2)中M1与硼烷-N,N-二乙基苯胺的摩尔比为1:0.2~1:2。
6.根据权利要求5所述的制备方法,其特征在于,所述步骤(2)中M1与硼烷-N,N-二乙基苯胺的摩尔比为1:0.5~1:1。
7.根据权利要求1所述的制备方法,其特征在于,所述步骤(2)中各物质需要溶于有机溶剂中,所述有机溶剂选自四氢呋喃、2-甲基四氢呋喃或1,4-二氧六环中的一种或多种。
8.根据权利要求7所述的制备方法,其特征在于,所述有机溶剂为四氢呋喃。
9.根据权利要求1所述的制备方法,其特征在于,所述步骤(2)的具体步骤为:
反应瓶中加入有机溶剂、(1S,2R)-(-)-1-氨基-2-茚醇,降温至-5~0℃搅拌,缓慢加入硼烷-N,N-二乙基苯胺,继续保温,获得溶液A;另将M1溶解于有机溶剂中,缓慢滴加至溶液A中,滴毕,室温反应;然后减压蒸干溶剂,加入乙酸乙酯50ml,用质量浓度为10%的硫酸洗涤,分液,有机层减压蒸干,得到白色固体,即中间体M2。
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