CN1680328A - A kind of preparation method of aripiprazole - Google Patents
A kind of preparation method of aripiprazole Download PDFInfo
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- CN1680328A CN1680328A CN 200510023211 CN200510023211A CN1680328A CN 1680328 A CN1680328 A CN 1680328A CN 200510023211 CN200510023211 CN 200510023211 CN 200510023211 A CN200510023211 A CN 200510023211A CN 1680328 A CN1680328 A CN 1680328A
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- CEUORZQYGODEFX-UHFFFAOYSA-N Aripirazole Chemical compound ClC1=CC=CC(N2CCN(CCCCOC=3C=C4NC(=O)CCC4=CC=3)CC2)=C1Cl CEUORZQYGODEFX-UHFFFAOYSA-N 0.000 title claims description 21
- 229960004372 aripiprazole Drugs 0.000 title claims description 21
- 238000002360 preparation method Methods 0.000 title claims description 20
- 238000006243 chemical reaction Methods 0.000 claims abstract description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 30
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical group CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 17
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 16
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- KRICLZOCASGBRD-UHFFFAOYSA-N 7-(4-hydroxybutoxy)-3,4-dihydro-1h-quinolin-2-one Chemical compound C1CC(=O)NC2=CC(OCCCCO)=CC=C21 KRICLZOCASGBRD-UHFFFAOYSA-N 0.000 claims description 11
- 239000003960 organic solvent Substances 0.000 claims description 11
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Substances [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 10
- 239000003513 alkali Substances 0.000 claims description 9
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 7
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- LKLSFDWYIBUGNT-UHFFFAOYSA-N 7-hydroxy-3,4-dihydro-1h-quinolin-2-one Chemical compound C1CC(=O)NC2=CC(O)=CC=C21 LKLSFDWYIBUGNT-UHFFFAOYSA-N 0.000 claims description 5
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 239000011230 binding agent Substances 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- HXHGULXINZUGJX-UHFFFAOYSA-N 4-chlorobutanol Chemical class OCCCCCl HXHGULXINZUGJX-UHFFFAOYSA-N 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- -1 aryl SULPHURYL CHLORIDE Chemical compound 0.000 claims description 3
- 239000002585 base Substances 0.000 claims description 3
- 239000012359 Methanesulfonyl chloride Substances 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 150000007530 organic bases Chemical class 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims 1
- 229910052500 inorganic mineral Inorganic materials 0.000 claims 1
- 239000011707 mineral Substances 0.000 claims 1
- 238000002425 crystallisation Methods 0.000 abstract 1
- 230000008025 crystallization Effects 0.000 abstract 1
- 238000004519 manufacturing process Methods 0.000 abstract 1
- 238000000034 method Methods 0.000 description 10
- 239000011734 sodium Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N 1-butanol Substances CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- ULTHEAFYOOPTTB-UHFFFAOYSA-N 1,4-dibromobutane Chemical compound BrCCCCBr ULTHEAFYOOPTTB-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000000018 receptor agonist Substances 0.000 description 2
- 229940044601 receptor agonist Drugs 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- UDQMXYJSNNCRAS-UHFFFAOYSA-N 2,3-dichlorophenylpiperazine Chemical compound ClC1=CC=CC(N2CCNCC2)=C1Cl UDQMXYJSNNCRAS-UHFFFAOYSA-N 0.000 description 1
- SIJLYRDVTMMSIP-UHFFFAOYSA-N 4-Bromo-1-butanol Chemical compound OCCCCBr SIJLYRDVTMMSIP-UHFFFAOYSA-N 0.000 description 1
- 102100022738 5-hydroxytryptamine receptor 1A Human genes 0.000 description 1
- 101710138638 5-hydroxytryptamine receptor 1A Proteins 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 101150049660 DRD2 gene Proteins 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 206010026749 Mania Diseases 0.000 description 1
- 208000021384 Obsessive-Compulsive disease Diseases 0.000 description 1
- 201000001880 Sexual dysfunction Diseases 0.000 description 1
- 230000000561 anti-psychotic effect Effects 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 229940124811 psychiatric drug Drugs 0.000 description 1
- 150000007660 quinolones Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 231100000872 sexual dysfunction Toxicity 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 208000019116 sleep disease Diseases 0.000 description 1
- 208000022925 sleep disturbance Diseases 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Description
技术领域Technical field
本发明涉及医药技术领域，是7-[4-[4-(2，3-二氯苯基)-1-哌嗪]丁氧基]-3，4-二氢-2(1H)-喹诺酮(阿立哌唑)的一种化学合成新方法。The invention relates to the technical field of medicine, which is 7-[4-[4-(2,3-dichlorophenyl)-1-piperazine]butoxy]-3,4-dihydro-2(1H)-quinolone (Aripiprazole) a new chemical synthesis method.
背景技术 Background technique
阿立哌唑是一种用于治疗恐慌、强迫症、睡眠障碍、性功能障碍、抑郁、焦虑或躁狂等精神分裂症的精神病药物，目前已在多个国家批准上市。阿立哌唑是喹诺酮衍生物，是第三代新型的抗精神病药物，它是部分D2受体激动剂，并伴有部分5HT1a受体激动剂及5TH2a受体拮抗剂。其化学结构式如下：Aripiprazole is a psychiatric drug used to treat schizophrenia such as panic, obsessive-compulsive disorder, sleep disturbance, sexual dysfunction, depression, anxiety or mania, and has been approved for marketing in many countries. Aripiprazole is a quinolone derivative and a third-generation new antipsychotic drug. It is a partial D2 receptor agonist, accompanied by a partial 5HT1a receptor agonist and 5TH2a receptor antagonist. Its chemical structural formula is as follows:
EP367141A2、US4234585公开了阿立哌唑如下的合成方法：EP367141A 2 and US4234585 disclose the following synthesis method of aripiprazole:
路线1Route 1
路线2：Route 2:
上述合成方法，均以7-羟基-3，4-二氢-2(1H)-喹诺酮为原料，以1，4-二溴丁烷为取代试剂来制备阿立哌唑，其缺点在于1，4-二溴丁烷用量大(三当量)，副产物较多，纯化复杂，故收率较低，收率往往不超过30％。Above-mentioned synthetic method, all take 7-hydroxyl-3,4-dihydro-2 (1H)-quinolone as raw material, prepare aripiprazole with 1,4-dibromobutane as substituting reagent, and its shortcoming is 1, The amount of 4-dibromobutane is large (three equivalents), the by-products are more, and the purification is complicated, so the yield is low, and the yield is often not more than 30%.
发明内容Contents of the invention
本发明提供一种纯化方便、得率高的合成阿立哌唑的新方法。本发明的关键是以4-卤-1-丁醇作为取代试剂代替了1，4-二溴丁烷，其与7-羟基-3，4-二氢-2(1H)-喹诺酮的反应，所得产物极性增大，易结晶纯化，而且羟基可进一步制成磺酸酯，以磺酸酯作为离去基团，使反应更容易进行，副反应少，产物纯度高。本发明制备方法操作简便，得率高，适于工业化大生产。The invention provides a new method for synthesizing aripiprazole with convenient purification and high yield. The key of the present invention is to replace 1,4-dibromobutane with 4-halo-1-butanol as a substituting reagent, and its reaction with 7-hydroxyl-3,4-dihydro-2(1H)-quinolone, The obtained product has increased polarity, is easy to crystallize and purify, and the hydroxyl group can be further made into a sulfonate. Using the sulfonate as a leaving group makes the reaction easier, with fewer side reactions and high product purity. The preparation method of the invention is simple and convenient to operate, has high yield and is suitable for large-scale industrial production.
本发明用4-卤-1-丁醇作为取代试剂制备阿立哌唑的合成路线如下：The present invention uses 4-halo-1-butanol as a substitute reagent to prepare the synthetic route of aripiprazole as follows:
其中X选自Cl、Br；Wherein X is selected from Cl, Br;
R选自苯、甲苯、甲基、乙基；R is selected from benzene, toluene, methyl, ethyl;
所说的碱可以为无机碱，选自K2CO3、Na2CO3、NaOH、KOH；也可以是有机碱，选自三乙胺、吡啶。The base may be an inorganic base selected from K 2 CO 3 , Na 2 CO 3 , NaOH, KOH; or an organic base selected from triethylamine and pyridine.
具体步骤为：The specific steps are:
1、制备7-(4-羟基丁氧基)-3，4-二氢-2(1H)-喹诺酮1. Preparation of 7-(4-hydroxybutoxy)-3,4-dihydro-2(1H)-quinolone
将7-羟基-3，4-二氢-2(1H)-喹诺酮和4-卤-1-丁醇在水或有机溶剂中进行反应，有机溶剂选自丙酮、乙腈、甲苯；反应温度为20℃～120℃，催化剂选自KI或NaI。7-Hydroxy-3,4-dihydro-2(1H)-quinolone and 4-halo-1-butanol are reacted in water or an organic solvent, and the organic solvent is selected from acetone, acetonitrile, toluene; the reaction temperature is 20 ℃～120℃, the catalyst is selected from KI or NaI.
2、制备7-(4-烷基或芳基磺酸酯基丁氧基)-3，4-二氢-2(1H)-喹诺酮2. Preparation of 7-(4-alkyl or arylsulfonate butoxy)-3,4-dihydro-2(1H)-quinolone
将7-(4-羟基丁氧基)-3，4-二氢-2(1H)-喹诺酮与烷基或芳基磺酰氯在有机溶剂中进行反应，有机溶剂选自乙酸乙酯、二氯甲烷、氯仿、二氯乙烷；可用碱或不用碱作为缚酸剂，碱选自K2CO3、Na2CO3、NaOH、KOH、三乙胺、吡啶。React 7-(4-hydroxybutoxy)-3,4-dihydro-2(1H)-quinolone with alkyl or arylsulfonyl chloride in an organic solvent, the organic solvent is selected from ethyl acetate, dichloro Methane, chloroform, dichloroethane; alkali or no alkali can be used as the acid-binding agent, and the alkali is selected from K 2 CO 3 , Na 2 CO 3 , NaOH, KOH, triethylamine, and pyridine.
3、制备阿立哌唑3. Preparation of Aripiprazole
将7-(4-烷基或芳基磺酸酯基丁氧基)-3，4-二氢-2(1H)-喹诺酮与4-(2，3-二氯苯基)哌嗪在有机溶剂中进行反应，有机溶剂选自丙酮、乙腈、甲苯；反应温度为20℃～120℃；可用或不用碱作为缚酸剂，碱选自K2CO3、Na2CO3、NaOH、KOH、三乙胺、吡啶。7-(4-alkyl or arylsulfonate butoxy)-3,4-dihydro-2(1H)-quinolone and 4-(2,3-dichlorophenyl)piperazine in organic The reaction is carried out in a solvent, and the organic solvent is selected from acetone, acetonitrile, and toluene; the reaction temperature is 20 ° C to 120 ° C; the acid-binding agent can be used or not, and the base is selected from K 2 CO 3 , Na 2 CO 3 , NaOH, KOH, Triethylamine, pyridine.
具体实施方式 Detailed ways
现结合实施例对本发明作详细描述，但本发明并不只限于此。The present invention will now be described in detail in conjunction with the embodiments, but the present invention is not limited thereto.
实施例1.制备7-(4-羟基丁氧基)-3，4-二氢-2(1H)-喹诺酮Example 1. Preparation of 7-(4-hydroxybutoxy)-3,4-dihydro-2(1H)-quinolones
将7-羟基-3，4-二氢-2(1H)-喹诺酮16.3g和4-氯-1-丁醇16g加到含有20gK2CO3的100ml乙腈中，回流搅拌反应10h，TLC检视，反应完成，按常规，减压蒸去乙腈，余物加入水，用二氯甲烷萃取，无水Na2SO4干燥，过滤，蒸去溶剂，用乙酸乙酯重结晶，得7-(4-羟基丁氧基)-3，4-二氢-2(1H)-喹诺酮21g，收率89％，mp 130～132℃。1HNMR(CDCl3)δ：1.719～1.777(m，2H)，1.831～1.898(m，2H)，2.587～2.625(m，2H)，2.861～2.900(t，2H)，3.695～3.738(m，2H)，3.965～3.997(t，2H)，6.369～6.375(d，1H)，6.500～6.527(m，1H)，7.010～7.031(d，1H)，8.573(s，1H)。MS m/z：235(M+)。Add 16.3 g of 7-hydroxy-3,4-dihydro-2(1H)-quinolone and 16 g of 4-chloro-1-butanol to 100 ml of acetonitrile containing 20 g K 2 CO 3 , reflux and stir for 10 h, and observe by TLC. After the reaction was completed, acetonitrile was evaporated under reduced pressure as usual, the residue was added to water, extracted with dichloromethane, dried over anhydrous Na 2 SO 4 , filtered, the solvent was evaporated, and recrystallized with ethyl acetate to obtain 7-(4- Hydroxybutoxy)-3,4-dihydro-2(1H)-quinolone 21g, yield 89%, mp 130-132°C. 1 HNMR (CDCl 3 ) δ: 1.719～1.777(m, 2H), 1.831～1.898(m, 2H), 2.587～2.625(m, 2H), 2.861～2.900(t, 2H), 3.695～3.738(m, 2H), 3.965~3.997(t, 2H), 6.369~6.375(d, 1H), 6.500~6.527(m, 1H), 7.010~7.031(d, 1H), 8.573(s, 1H). MS m/z: 235 (M + ).
实施例2.制备7-(4-羟基丁氧基)-3，4-二氢-2(1H)-喹诺酮Example 2. Preparation of 7-(4-hydroxybutoxy)-3,4-dihydro-2(1H)-quinolones
方法同实施例1，不同之处在于用4-溴-1-丁醇代替4-氯-1-丁醇，得7-(4-羟基丁氧基)-3，4-二氢-2(1H)-喹诺酮，收率92.2％。Method is the same as in Example 1, except that 4-bromo-1-butanol is used to replace 4-chloro-1-butanol to obtain 7-(4-hydroxybutoxy)-3,4-dihydro-2( 1H)-quinolone, yield 92.2%.
实施例3.制备7-(4-羟基丁氧基)-3，4-二氢-2(1H)-喹诺酮Example 3. Preparation of 7-(4-hydroxybutoxy)-3,4-dihydro-2(1H)-quinolone
方法同实施例1，不同之处在于用丙酮代替乙腈，反应液中加入NaI作为催化剂，室温搅拌，结果得产物7-(4-羟基丁氧基)-3，4-二氢-2(1H)-喹诺酮，收率88％。The method is the same as in Example 1, except that acetone is used instead of acetonitrile, NaI is added as a catalyst in the reaction solution, stirred at room temperature, and the product 7-(4-hydroxybutoxy)-3,4-dihydro-2(1H )-quinolone, yield 88%.
实施例4.制备7-(4-对甲苯磺酸酯基丁氧基)-3，4-二氢-2(1H)-喹诺酮Example 4. Preparation of 7-(4-tosylate butoxy)-3,4-dihydro-2(1H)-quinolone
将实施例1制得的7-(4-羟基丁氧基)-3，4-二氢-2(1H)-喹诺酮15g加到含100ml二氯甲烷和10ml三乙胺的混合溶液中，再将对甲苯磺酰氯12.7g溶于50ml二氯甲烷后滴加到上述溶液中，室温反应5h，按常规，反应液先用水洗，再用饱和碳酸钠水溶液洗，无水Na2SO4干燥，过滤，蒸去溶剂，用乙酸乙酯重结晶，得7-(4-对甲苯磺酸酯基丁氧基)-3，4-二氢-2(1H)-喹诺酮23g，收率95％，mp 111～112℃。1HN(CDCl3)δ：1.733～1.853(m，4H)，2.434(s，3H)，2.584～2.623(m，2H)，2.861～2.898(t，2H)，3.872～3.901(t，2H)，4.095～4.125(t，2H)，6.320～6.325(d，1H)，6.439～6.466(m，1H)，7.000～7.021(d，1H)，7.323～7.343(d，2H)，7.780～7.800(d，2H)，8.600(s，1H)。MS m/z：389(M+)。7-(4-hydroxybutoxy)-3,4-dihydro-2(1H)-quinolone 15g that embodiment 1 makes is added in the mixed solution that contains 100ml dichloromethane and 10ml triethylamine, then Dissolve 12.7 g of p-toluenesulfonyl chloride in 50 ml of dichloromethane and add it dropwise to the above solution, and react at room temperature for 5 hours. As usual, the reaction solution is washed with water first, then with saturated aqueous sodium carbonate solution, and dried over anhydrous Na 2 SO 4 . Filtrate, distill off the solvent, and recrystallize from ethyl acetate to obtain 23 g of 7-(4-p-toluenesulfonate butoxy)-3,4-dihydro-2(1H)-quinolone with a yield of 95%. mp 111-112°C. 1 HN(CDCl 3 )δ: 1.733～1.853(m, 4H), 2.434(s, 3H), 2.584～2.623(m, 2H), 2.861～2.898(t, 2H), 3.872～3.901(t, 2H) , 4.095～4.125(t, 2H), 6.320～6.325(d, 1H), 6.439～6.466(m, 1H), 7.000～7.021(d, 1H), 7.323～7.343(d, 2H), 7.780～7.800( d, 2H), 8.600 (s, 1H). MS m/z: 389 (M + ).
实施例5.制备7-(4-甲烷磺酸酯基丁氧基)-3，4-二氢-2(1H)-喹诺酮Example 5. Preparation of 7-(4-methanesulfonate butoxy)-3,4-dihydro-2(1H)-quinolone
方法同实施例4，不同之处在于用甲烷磺酰氯替代对甲苯磺酰氯，结果得产物7-(4-甲烷磺酸酯基丁氧基)-3，4-二氢-2(1H)-喹诺酮，收率91％。The method is the same as in Example 4, except that methanesulfonyl chloride is used instead of p-toluenesulfonyl chloride, resulting in product 7-(4-methanesulfonate butoxy)-3,4-dihydro-2(1H)- Quinolones, yield 91%.
实施例6.制备7-(4-对甲苯磺酸酯基丁氧基)-3，4-二氢-2(1H)-喹诺酮Example 6. Preparation of 7-(4-tosylate butoxy)-3,4-dihydro-2(1H)-quinolone
方法同实施例4，不同之处在于氯仿代替二氯甲烷，Na2CO3替代三乙胺，得产物7-(4-对甲苯磺酸酯基丁氧基)-3，4-二氢-2(1H)-喹诺酮，收率89％。The method is the same as in Example 4, except that chloroform is substituted for dichloromethane, Na 2 CO 3 is substituted for triethylamine, and the product 7-(4-tosylate butoxy)-3,4-dihydro- 2(1H)-quinolone, the yield is 89%.
实施例7.制备阿立哌唑Example 7. Preparation of Aripiprazole
将实施例4制得的7-(4-对甲苯磺酸酯基丁氧基)-3，4-二氢-2(1H)-喹诺酮20g和4-(2，3-二氯苯基)哌嗪12g加入200ml乙腈中，加入10.64g K2CO3，加热回流，机械搅拌，反应4h，过滤，滤液减压回收乙腈，用无水乙醇重结晶，得阿立哌唑21.8g，收率95％，mp138～140℃。1H-NMR(DMSO-d6，TMS)δ：1.545～1.618(m，2H)，1.691～1.743(m，2H)，2.370～2.427(m，4H)，2.498～2.531(m，4H)，2.758～2.795(t，2H)，2.962～2.984(t，4H)，3.907～3.939(t，2H)，6.445～6.494(m，2H)，7.019～7.039(d，1H)，7.106～7.131(m，1H)，7.261～7.313(m，2H)，9.916(s，1H)。20 g of 7-(4-tosylate butoxy)-3,4-dihydro-2(1H)-quinolone and 4-(2,3-dichlorophenyl) prepared in Example 4 Add 12 g of piperazine to 200 ml of acetonitrile, add 10.64 g of K 2 CO 3 , heat to reflux, stir mechanically, react for 4 h, filter, recover acetonitrile from the filtrate under reduced pressure, and recrystallize with absolute ethanol to obtain 21.8 g of aripiprazole, yield 95%, mp 138-140°C. 1 H-NMR (DMSO-d 6 , TMS) δ: 1.545-1.618 (m, 2H), 1.691-1.743 (m, 2H), 2.370-2.427 (m, 4H), 2.498-2.531 (m, 4H), 2.758～2.795(t, 2H), 2.962～2.984(t, 4H), 3.907～3.939(t, 2H), 6.445～6.494(m, 2H), 7.019～7.039(d, 1H), 7.106～7.131(m , 1H), 7.261~7.313 (m, 2H), 9.916 (s, 1H).
实施例8.制备阿立哌唑Example 8. Preparation of Aripiprazole
方法同实施例7，不同之处在于将实施例5制得的7-(4-甲烷磺酸酯基丁氧基)-3，4-二氢-2(1H)-喹诺酮代替7-(4-对甲苯磺酸酯基丁氧基)-3，4-二氢-2(1H)-喹诺酮，制得阿立哌唑，收率92.6％。The method is the same as in Example 7, except that the 7-(4-methanesulfonate butoxy)-3,4-dihydro-2(1H)-quinolone obtained in Example 5 is replaced by 7-(4 - p-toluenesulfonate butoxy)-3,4-dihydro-2(1H)-quinolone to prepare aripiprazole with a yield of 92.6%.
实施例9.制备阿立哌唑Example 9. Preparation of Aripiprazole
方法同实施例7，不同之处在于将丙酮代替乙腈，吡啶代替K2CO3，室温反应，制得阿立哌唑，收率89％。The method is the same as in Example 7, except that acetone is replaced by acetonitrile, pyridine is replaced by K 2 CO 3 , and the reaction is carried out at room temperature to prepare aripiprazole with a yield of 89%.
经计算，上述各实施例制备的阿立哌唑总得率为70～85％，比现有制备阿立哌唑的方法得率高。According to calculations, the total yield of aripiprazole prepared in the above examples is 70-85%, which is higher than that of the existing methods for preparing aripiprazole.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103214415A (en) * | 2013-05-09 | 2013-07-24 | 江苏万全特创医药生物技术有限公司 | Preparation method of aripiprazole and key intermediate of aripiprazole |
| CN105712930A (en) * | 2014-12-02 | 2016-06-29 | 翰宇药业（武汉）有限公司 | Aripiprazole and aripiprazole intermediate synthesis method |
| CN108069900A (en) * | 2016-11-08 | 2018-05-25 | 齐鲁制药有限公司 | The preparation method and purposes of Aripiprazole hydrochloride |
| CN109251172A (en) * | 2018-10-11 | 2019-01-22 | 暨明医药科技（苏州）有限公司 | A kind of synthetic method of Aripiprazole |
| CN115594630A (en) * | 2021-07-08 | 2023-01-13 | 北京万全德众医药生物技术有限公司（Cn） | Preparation method of aripiprazole key intermediate |
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| US5006528A (en) * | 1988-10-31 | 1991-04-09 | Otsuka Pharmaceutical Co., Ltd. | Carbostyril derivatives |
| WO2004063162A1 (en) * | 2003-01-09 | 2004-07-29 | Otsuka Pharmaceutical Co., Ltd. | Process for preparing aripiprazole |
| CN1263740C (en) * | 2003-08-08 | 2006-07-12 | 江苏吴中苏药医药开发有限责任公司 | Pot cooking sythesis method of alipyracole |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103214415A (en) * | 2013-05-09 | 2013-07-24 | 江苏万全特创医药生物技术有限公司 | Preparation method of aripiprazole and key intermediate of aripiprazole |
| CN105712930A (en) * | 2014-12-02 | 2016-06-29 | 翰宇药业（武汉）有限公司 | Aripiprazole and aripiprazole intermediate synthesis method |
| CN108069900A (en) * | 2016-11-08 | 2018-05-25 | 齐鲁制药有限公司 | The preparation method and purposes of Aripiprazole hydrochloride |
| CN108069900B (en) * | 2016-11-08 | 2022-09-23 | 齐鲁制药有限公司 | Preparation method and application of aripiprazole hydrochloride |
| CN109251172A (en) * | 2018-10-11 | 2019-01-22 | 暨明医药科技（苏州）有限公司 | A kind of synthetic method of Aripiprazole |
| CN109251172B (en) * | 2018-10-11 | 2022-04-01 | 暨明医药科技（苏州）有限公司 | Synthesis method of aripiprazole |
| CN115594630A (en) * | 2021-07-08 | 2023-01-13 | 北京万全德众医药生物技术有限公司（Cn） | Preparation method of aripiprazole key intermediate |
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