CN116375594A - 一种依喜替康中间体制备工艺 - Google Patents
一种依喜替康中间体制备工艺 Download PDFInfo
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- 229960004768 irinotecan Drugs 0.000 title claims abstract description 16
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 title claims abstract description 16
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
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- 239000000047 product Substances 0.000 claims abstract description 17
- 239000012043 crude product Substances 0.000 claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims description 75
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 66
- 238000005406 washing Methods 0.000 claims description 48
- 238000003756 stirring Methods 0.000 claims description 45
- 238000001914 filtration Methods 0.000 claims description 42
- 238000001035 drying Methods 0.000 claims description 39
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 36
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 27
- 238000001816 cooling Methods 0.000 claims description 24
- 239000012065 filter cake Substances 0.000 claims description 24
- 238000010438 heat treatment Methods 0.000 claims description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- 238000002425 crystallisation Methods 0.000 claims description 18
- 230000008025 crystallization Effects 0.000 claims description 18
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 15
- 230000007062 hydrolysis Effects 0.000 claims description 15
- 238000006460 hydrolysis reaction Methods 0.000 claims description 15
- 239000000203 mixture Substances 0.000 claims description 15
- 239000012074 organic phase Substances 0.000 claims description 15
- 239000003208 petroleum Substances 0.000 claims description 15
- 239000000463 material Substances 0.000 claims description 12
- 150000007524 organic acids Chemical class 0.000 claims description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 12
- 238000005070 sampling Methods 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 9
- 239000000706 filtrate Substances 0.000 claims description 9
- 230000007935 neutral effect Effects 0.000 claims description 9
- 238000010992 reflux Methods 0.000 claims description 9
- 230000001105 regulatory effect Effects 0.000 claims description 9
- 239000007787 solid Substances 0.000 claims description 9
- RDWYSVCUOZOEBC-UHFFFAOYSA-N 4-(4-fluoro-3-methylphenyl)-4-oxobutanoic acid Chemical compound CC1=CC(C(=O)CCC(O)=O)=CC=C1F RDWYSVCUOZOEBC-UHFFFAOYSA-N 0.000 claims description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- JQJPBYFTQAANLE-UHFFFAOYSA-N Butyl nitrite Chemical compound CCCCON=O JQJPBYFTQAANLE-UHFFFAOYSA-N 0.000 claims description 6
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 230000001276 controlling effect Effects 0.000 claims description 6
- 239000013078 crystal Substances 0.000 claims description 6
- 238000002386 leaching Methods 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- 239000012071 phase Substances 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 6
- 239000012286 potassium permanganate Substances 0.000 claims description 6
- DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 claims description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 6
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 claims description 6
- WFFPQKXBJLTVSA-UHFFFAOYSA-N 4-(2-acetamido-4-fluoro-5-methylphenyl)butanoic acid Chemical compound CC(=O)NC1=CC(F)=C(C)C=C1CCCC(O)=O WFFPQKXBJLTVSA-UHFFFAOYSA-N 0.000 claims description 3
- FULMKQGHCXYECN-UHFFFAOYSA-N 4-(4-fluoro-3-methylphenyl)butanoic acid Chemical compound CC1=CC(CCCC(O)=O)=CC=C1F FULMKQGHCXYECN-UHFFFAOYSA-N 0.000 claims description 3
- JHLCJNGILQUGDT-UHFFFAOYSA-N 7-fluoro-6-methyl-3,4-dihydro-2h-naphthalen-1-one Chemical compound C1CCC(=O)C2=C1C=C(C)C(F)=C2 JHLCJNGILQUGDT-UHFFFAOYSA-N 0.000 claims description 3
- YWJAMZCHGKPQNH-UHFFFAOYSA-N 8-fluoro-7-methyl-3,4-dihydro-1-benzazepin-2-one Chemical compound C1CC(=O)N=C2C=C(F)C(C)=CC2=C1 YWJAMZCHGKPQNH-UHFFFAOYSA-N 0.000 claims description 3
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 3
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 claims description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 3
- 150000008065 acid anhydrides Chemical class 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 3
- 125000003963 dichloro group Chemical group Cl* 0.000 claims description 3
- 238000007865 diluting Methods 0.000 claims description 3
- 238000004090 dissolution Methods 0.000 claims description 3
- 239000005457 ice water Substances 0.000 claims description 3
- RSIIDEXJEKVHHH-UHFFFAOYSA-N n-(3-fluoro-4-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide Chemical compound C1CCCC2=C1C(C)=C(F)C=C2NC(=O)C RSIIDEXJEKVHHH-UHFFFAOYSA-N 0.000 claims description 3
- OMNUGNSWHKWBST-UHFFFAOYSA-N n-(3-fluoro-4-methyl-5-oxo-7,8-dihydro-6h-naphthalen-1-yl)acetamide Chemical compound O=C1CCCC2=C1C(C)=C(F)C=C2NC(=O)C OMNUGNSWHKWBST-UHFFFAOYSA-N 0.000 claims description 3
- PSNRFAKPOCIEDV-UHFFFAOYSA-N n-(3-fluoro-4-methyl-8-oxo-6,7-dihydro-5h-naphthalen-1-yl)acetamide Chemical compound C1CCC(=O)C2=C1C(C)=C(F)C=C2NC(=O)C PSNRFAKPOCIEDV-UHFFFAOYSA-N 0.000 claims description 3
- SFKOVHWIFAYBLY-UHFFFAOYSA-N n-(7-fluoro-6-methyl-3,4-dihydro-2h-naphthalen-1-ylidene)hydroxylamine Chemical compound C1CCC(=NO)C2=C1C=C(C)C(F)=C2 SFKOVHWIFAYBLY-UHFFFAOYSA-N 0.000 claims description 3
- UNQLSBJKEGXCGH-UHFFFAOYSA-N n-(8-acetamido-6-fluoro-5-methyl-1-oxo-3,4-dihydro-2h-naphthalen-2-yl)acetamide Chemical compound FC1=CC(NC(C)=O)=C2C(=O)C(NC(=O)C)CCC2=C1C UNQLSBJKEGXCGH-UHFFFAOYSA-N 0.000 claims description 3
- SEFPQWAVZCZXTK-UHFFFAOYSA-N n-(8-amino-6-fluoro-5-methyl-1-oxo-3,4-dihydro-2h-naphthalen-2-yl)acetamide Chemical compound FC1=CC(N)=C2C(=O)C(NC(=O)C)CCC2=C1C SEFPQWAVZCZXTK-UHFFFAOYSA-N 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 238000005191 phase separation Methods 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- 239000000843 powder Substances 0.000 claims description 3
- 230000001376 precipitating effect Effects 0.000 claims description 3
- 238000010791 quenching Methods 0.000 claims description 3
- 230000000171 quenching effect Effects 0.000 claims description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 3
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 claims description 3
- 239000004289 sodium hydrogen sulphite Substances 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- 238000000967 suction filtration Methods 0.000 claims description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 3
- 230000001502 supplementing effect Effects 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 238000000034 method Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical class C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/10—Preparation of carboxylic acid amides from compounds not provided for in groups C07C231/02 - C07C231/08
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/14—Preparation of carboxylic acid amides by formation of carboxamide groups together with reactions not involving the carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/083—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid anhydrides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/377—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/16—Benzazepines; Hydrogenated benzazepines
-
- 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
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
本发明公开了一种依喜替康中间体制备工艺,具体步骤如下:1)合成中间体A1;2)合成中间体A2;3)合成中间体A3;4)合成中间体A4;5)合成中间体A5;6)合成中间体A6;7)合成中间体A7;8)合成中间体A8;9)合成中间体A9;10)合成中间体A10;11)合成依喜替康中间体成品粗品。本发明制备方法得到的依喜替康中间体产率高,纯度好,大大降低生产成本。
Description
技术领域
本发明涉及依喜替康中间体制造技术领域,具体涉及一种依喜替康中间体制备工艺。
背景技术
依喜替康(ExatecanMesilate)作为一种药物喜树碱类衍生物,其常在液体制剂的制备过程中作为活性成分使用。
目前的依喜替康中间体合成工艺由于工艺粗放,副反应较多,合成产物中杂质含量大,无法满足后续精细制药的要求。
有鉴于此,特提出本发明。
发明内容
本发明的目的是提供一种依喜替康中间体制备工艺,本发明的制备方法得到的依喜替康中间体产率高,纯度好,大大降低生产成本。
为解决上述技术问题,本发明采用如下技术方案:
本发明提供一种依喜替康中间体制备工艺,其特征在于,具体步骤如下:
1)合成中间体A1:将CAS:349-22-4和C11H11FO3进行胡克反应,在20℃反应13小时,再在30℃反应10小时,冷却,将反应液慢慢加入水和浓盐酸的水解釜中,水解温度不超过35℃,完毕后搅拌35分钟,静止分层,酸相再用有机溶剂萃取,用36%盐酸洗涤,减压浓缩并回收溶剂,残物加入氯仿回流溶解,冷却析出结晶,冷却4-6℃过滤,滤饼用水淋洗,90℃干燥,控制水份小于0.5%以下;所述A1为4-(4-氟-3-甲基苯基)-4-氧代丁酸;
A1反应式如下:
2)合成中间体A2:将步骤1得到的A1溶于有机酸中,然后于80℃以下滴加有机物,完毕后于90℃反应,3小时后取样,反应结束后减压浓缩有机酸,残物稀释到冰水中,有机相,减压浓缩并回收乙酸乙酯,残物搅拌下加入石油醚于55℃析出结晶粉末,冷至15℃过滤;滤饼用石油醚淋洗,干燥后即得成品A2;所述A2为4-(4-氟-3-甲基苯基)丁酸;
A2反应式如下:
3)合成中间体A3:将物料A2于12℃均分三次搅拌下加入到浓硫酸中,完毕后在此温下搅拌反应21-23小时,待水解;另一反应釜中加入碎冰和水搅拌下慢慢加入上述物料;控制温度不超过55℃,完毕后搅拌0.5小时并升至室温过滤,水洗至中性称潮品重量;所述A3为7-氟-6-甲基-1-四氢萘酮;
4)合成中间体A4:将中间体A3加入到有机溶剂、羟胺物料中,升温于 55℃微回流反应24小时,反应结束后,减压浓缩并回收溶剂,残物加水搅拌析晶,过滤,滤饼充分水洗,95℃减压干燥;所述A4为7-氟-6-甲基-1-四氢萘酮肟;
A4反应式如下:
5)合成中间体A5:反应釜中,加入35%磷酸,加热控制温度在60℃以下,均分3次加入粉末状五氧化磷,待固体全溶后均分3次加入中间体A4,并在60℃反应15-17小时,冷却至20℃加水水解,完毕后搅拌0.4-0.6小时,抽滤,洗涤至中性,干燥后得中间体A5;所述A5为3,4-二氢-8-氟-7-甲基-2-氧代 -1-苯并吖庚因;
A5反应式如下:
6)合成中间体A6:反应釜中加入醇、浓盐酸及中间体A5,回流反应,减压浓缩弄回收醇,加入二氯代溶剂,待固体溶解后,加入三乙胺,冷却,于4-6℃滴加酸酸酐,然后升温至25—30℃反应4小时,加入水反应,用稀盐酸调节物料至中性,分出有机相,有机相用饱和碳酸氢钠溶液洗涤,减压浓缩,残物用稀酸调节物料PH6,用乙酸乙酯萃取,有机相用饱和氯化钠溶液洗涤,无水硫酸镁干燥,过滤,减压浓缩并回收乙酸乙酯,残物加入石油醚搅拌析晶,过滤, 80℃减压干燥,得中间体A6;所述A6为4-(2-乙酰氨基-4-氟-5-甲基苯基)丁酸;
A6反应式如下:
7)合成中间体A7:反应釜中加入二氯甲烷及中间体A6,冷却,于25℃内滴加氯化亚砜,完毕后在此温下反应0.4-0.6小时,再升温至30℃反应11小时,减压浓缩,残物在此加入等量的二氯甲烷,于3—6℃均分四次加入无水三氯化铝,间隔时间为10分钟,完毕后在同样的温度下搅拌反应1小时,升温于30℃反应24小时,取样反应结束后冷却于4-6℃加入定量5%盐酸,期间补充碎冰以控制温度,静止分相,酸相用氯仿萃取二次,合并有机相用饱和碳酸氢钠溶液洗涤二次,加入无水碳酸钾干燥,减压浓缩并回收溶剂,残物加入异丙醚搅拌析晶1小时,过滤,滤饼用异丙醚洗涤,50℃减压干燥,得中间体A7;所述A7为5-乙酰氨基-7-氟-8-甲基-1-四氢萘酮;
A7反应式如下:
8)合成中间体A8:反应釜中加入有机酸、A7及三乙基硅烷,于50℃反应 4小时,取样反应结束后,减压浓缩有机酸,残物加入石油醚搅拌析晶,10℃过滤,滤饼用石油醚洗涤,50℃减压干燥,得中间体A8;所述A8为5-乙酰氨基-7-氟-8-甲基-1,2,3,4-四氢化萘;
A8反应式如下:
9)合成中间体A9:反应釜中加入丙酮、中间体A8和小苏打,在10-15℃于4小时内分批加入高锰酸钾,升温至室温反应1小时取样,反应结束后加入 5%亚硫酸氢钠溶液消除未反应完的高锰酸钾;过滤,滤饼用预热至40—45℃的氯仿充分洗涤,减压浓缩滤液和洗涤液,残物再溶于氯仿,用饱和碳酸氢钠溶液洗涤三次,碳酸钾干燥,减压浓缩,残物加入乙醚搅拌析晶,10℃过滤,滤饼用乙醚洗涤,50℃减压干燥得中间体A9;所述A9为8-乙酰氨基-6-氟-5-甲基-1-四氢萘酮;
A9反应式如下:
10)合成中间体A10:反应釜中配有氮气导入装置,加入四氢呋喃和中间体A9,通氮待固体全溶后,于15℃滴加叔丁醇钾溶液,0.9-1.1小时加完,完毕后在相同的温度下反应0.5小时,在5—7℃滴加亚硝酸正丁酯,完毕后在相同温度下反应2小时,加水淬灭反应,用稀盐酸调节PH3-4,并充分搅拌0.5 小时,过滤,滤饼水洗至中性,65℃减压干燥,得棕色A10中间体;所述A10 为N,N'-(3-氟-4-甲基-8-氧代-5,6,7,8-四氢萘-1,7-二基)二乙酰胺;
A10反应式如下:
11)合成依喜替康中间体A11成品粗品:反应釜中,加入A10和20%盐酸,于58—60℃反应三小时,冷却至室温,加入水,搅拌15分钟,用铺设硅藻土的过滤装置过滤,滤液用670g水洗涤,合并滤液和洗涤液;反复多次用氯仿萃取,直至无产品萃出,浓缩残物加入乙醚析晶过滤,乙醚淋洗,干燥得成品粗品;所述A11为N-(8-氨基-6-氟-5-甲基-1-氧代-1,2,3,4-四氢萘-2-基)乙酰胺;
A11反应式如下:
本发明的有益效果在于:本发明的制备方法得到的依喜替康中间体产率高,纯度好,大大降低生产成本。
具体实施方式
下面将结合本发明实施例中对本发明的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
一种依喜替康中间体制备工艺,具体步骤如下:
1)合成中间体A1:将CAS:349-22-4和C11H11FO3进行胡克反应,在20℃反应13小时,再在30℃反应10小时,冷却,将反应液慢慢加入水和浓盐酸的水解釜中,水解温度不超过35℃,完毕后搅拌35分钟,静止分层,酸相再用有机溶剂萃取,用36%盐酸洗涤,减压浓缩并回收溶剂,残物加入氯仿回流溶解,冷却析出结晶,冷却4-6℃过滤,滤饼用水淋洗,90℃干燥,控制水份小于0.5%以下;所述A1为4-(4-氟-3-甲基苯基)-4-氧代丁酸;
A1反应式如下:
2)合成中间体A2:将步骤1得到的A1溶于有机酸中,然后于80℃以下滴加有机物,完毕后于90℃反应,3小时后取样,反应结束后减压浓缩有机酸,残物稀释到冰水中,有机相,减压浓缩并回收乙酸乙酯,残物搅拌下加入石油醚于55℃析出结晶粉末,冷至15℃过滤;滤饼用石油醚淋洗,干燥后即得成品A2;所述A2为4-(4-氟-3-甲基苯基)丁酸;
A2反应式如下:
3)合成中间体A3:将物料A2于12℃均分三次搅拌下加入到浓硫酸中,完毕后在此温下搅拌反应21-23小时,待水解;另一反应釜中加入碎冰和水搅拌下慢慢加入上述物料;控制温度不超过55℃,完毕后搅拌0.5小时并升至室温过滤,水洗至中性称潮品重量;所述A3为7-氟-6-甲基-1-四氢萘酮;
4)合成中间体A4:将中间体A3加入到有机溶剂、羟胺物料中,升温于 55℃微回流反应24小时,反应结束后,减压浓缩并回收溶剂,残物加水搅拌析晶,过滤,滤饼充分水洗,95℃减压干燥;所述A4为7-氟-6-甲基-1-四氢萘酮肟;
A4反应式如下:
5)合成中间体A5:反应釜中,加入35%磷酸,加热控制温度在60℃以下,均分3次加入粉末状五氧化磷,待固体全溶后均分3次加入中间体A4,并在 60℃反应15-17小时,冷却至20℃加水水解,完毕后搅拌0.4-0.6小时,抽滤,洗涤至中性,干燥后得中间体A5;所述A5为3,4-二氢-8-氟-7-甲基-2-氧代 -1-苯并吖庚因;
A5反应式如下:
6)合成中间体A6:反应釜中加入醇、浓盐酸及中间体A5,回流反应,减压浓缩弄回收醇,加入二氯代溶剂,待固体溶解后,加入三乙胺,冷却,于4-6℃滴加酸酸酐,然后升温至25—30℃反应4小时,加入水反应,用稀盐酸调节物料至中性,分出有机相,有机相用饱和碳酸氢钠溶液洗涤,减压浓缩,残物用稀酸调节物料PH6,用乙酸乙酯萃取,有机相用饱和氯化钠溶液洗涤,无水硫酸镁干燥,过滤,减压浓缩并回收乙酸乙酯,残物加入石油醚搅拌析晶,过滤, 80℃减压干燥,得中间体A6;所述A6为4-(2-乙酰氨基-4-氟-5-甲基苯基)丁酸;
A6反应式如下:
7)合成中间体A7:反应釜中加入二氯甲烷及中间体A6,冷却,于25℃内滴加氯化亚砜,完毕后在此温下反应0.4-0.6小时,再升温至30℃反应11小时,减压浓缩,残物在此加入等量的二氯甲烷,于3—6℃均分四次加入无水三氯化铝,间隔时间为10分钟,完毕后在同样的温度下搅拌反应1小时,升温于30℃反应24小时,取样反应结束后冷却于4-6℃加入定量5%盐酸,期间补充碎冰以控制温度,静止分相,酸相用氯仿萃取二次,合并有机相用饱和碳酸氢钠溶液洗涤二次,加入无水碳酸钾干燥,减压浓缩并回收溶剂,残物加入异丙醚搅拌析晶1小时,过滤,滤饼用异丙醚洗涤,50℃减压干燥,得中间体A7;所述A7为5-乙酰氨基-7-氟-8-甲基-1-四氢萘酮;
A7反应式如下:
8)合成中间体A8:反应釜中加入有机酸、A7及三乙基硅烷,于50℃反应 4小时,取样反应结束后,减压浓缩有机酸,残物加入石油醚搅拌析晶,10℃过滤,滤饼用石油醚洗涤,50℃减压干燥,得中间体A8;所述A8为5-乙酰氨基-7-氟-8-甲基-1,2,3,4-四氢化萘;
A8反应式如下:
9)合成中间体A9:反应釜中加入丙酮、中间体A8和小苏打,在10-15℃于4小时内分批加入高锰酸钾,升温至室温反应1小时取样,反应结束后加入5%亚硫酸氢钠溶液消除未反应完的高锰酸钾;过滤,滤饼用预热至40—45℃的氯仿充分洗涤,减压浓缩滤液和洗涤液,残物再溶于氯仿,用饱和碳酸氢钠溶液洗涤三次,碳酸钾干燥,减压浓缩,残物加入乙醚搅拌析晶,10℃过滤,滤饼用乙醚洗涤,50℃减压干燥得中间体A9;所述A9为8-乙酰氨基-6-氟-5-甲基-1-四氢萘酮;
A9反应式如下:
10)合成中间体A10:反应釜中配有氮气导入装置,加入四氢呋喃和中间体A9,通氮待固体全溶后,于15℃滴加叔丁醇钾溶液,0.9-1.1小时加完,完毕后在相同的温度下反应0.5小时,在5—7℃滴加亚硝酸正丁酯,完毕后在相同温度下反应2小时,加水淬灭反应,用稀盐酸调节PH3-4,并充分搅拌0.5 小时,过滤,滤饼水洗至中性,65℃减压干燥,得棕色A10中间体;所述A10 为N,N'-(3-氟-4-甲基-8-氧代-5,6,7,8-四氢萘-1,7-二基)二乙酰胺;
A10反应式如下:
11)合成依喜替康中间体A11成品粗品:反应釜中,加入A10和20%盐酸,于58—60℃反应三小时,冷却至室温,加入水,搅拌15分钟,用铺设硅藻土的过滤装置过滤,滤液用670g水洗涤,合并滤液和洗涤液;反复多次用氯仿萃取,直至无产品萃出,浓缩残物加入乙醚析晶过滤,乙醚淋洗,干燥得成品粗品;所述A11为N-(8-氨基-6-氟-5-甲基-1-氧代-1,2,3,4-四氢萘-2-基)乙酰胺;
A11反应式如下:
显然,本领域的技术人员可以对本发明进行各种改动和变型而不脱离本发明的精神和范围。这样,倘若本发明的这些修改和变型属于本发明权利要求及其等同技术的范围之内,则本发明也意图包含这些改动和变型在内。
Claims (1)
1.一种依喜替康中间体制备工艺,其特征在于,具体步骤如下:
1)合成中间体A1:将CAS:349-22-4和C11H11FO3进行胡克反应,在20℃反应13小时,再在30℃反应10小时,冷却,将反应液慢慢加入水和浓盐酸的水解釜中,水解温度不超过35℃,完毕后搅拌35分钟,静止分层,酸相再用有机溶剂萃取,用36%盐酸洗涤,减压浓缩并回收溶剂,残物加入氯仿回流溶解,冷却析出结晶,冷却4-6℃过滤,滤饼用水淋洗,90℃干燥,控制水份小于0.5%以下;所述A1为4-(4-氟-3-甲基苯基)-4-氧代丁酸;
A1反应式如下:
2)合成中间体A2:将步骤1得到的A1溶于有机酸中,然后于80℃以下滴加有机物,完毕后于90℃反应,3小时后取样,反应结束后减压浓缩有机酸,残物稀释到冰水中,有机相,减压浓缩并回收乙酸乙酯,残物搅拌下加入石油醚于55℃析出结晶粉末,冷至15℃过滤;滤饼用石油醚淋洗,干燥后即得成品A2;所述A2为4-(4-氟-3-甲基苯基)丁酸;
A2反应式如下:
3)合成中间体A3:将物料A2于12℃均分三次搅拌下加入到浓硫酸中,完毕后在此温下搅拌反应21-23小时,待水解;另一反应釜中加入碎冰和水搅拌下慢慢加入上述物料;控制温度不超过55℃,完毕后搅拌0.5小时并升至室温过滤,水洗至中性称潮品重量;所述A3为7-氟-6-甲基-1-四氢萘酮;
4)合成中间体A4:将中间体A3加入到有机溶剂、羟胺物料中,升温于55℃微回流反应24小时,反应结束后,减压浓缩并回收溶剂,残物加水搅拌析晶,过滤,滤饼充分水洗,95℃减压干燥;所述A4为7-氟-6-甲基-1-四氢萘酮肟;
A4反应式如下:
5)合成中间体A5:反应釜中,加入35%磷酸,加热控制温度在60℃以下,均分3次加入粉末状五氧化磷,待固体全溶后均分3次加入中间体A4,并在60℃反应15-17小时,冷却至20℃加水水解,完毕后搅拌0.4-0.6小时,抽滤,洗涤至中性,干燥后得中间体A5;所述A5为3,4-二氢-8-氟-7-甲基-2-氧代-1-苯并吖庚因;
A5反应式如下:
6)合成中间体A6:反应釜中加入醇、浓盐酸及中间体A5,回流反应,减压浓缩弄回收醇,加入二氯代溶剂,待固体溶解后,加入三乙胺,冷却,于4-6℃滴加酸酸酐,然后升温至25—30℃反应4小时,加入水反应,用稀盐酸调节物料至中性,分出有机相,有机相用饱和碳酸氢钠溶液洗涤,减压浓缩,残物用稀酸调节物料PH6,用乙酸乙酯萃取,有机相用饱和氯化钠溶液洗涤,无水硫酸镁干燥,过滤,减压浓缩并回收乙酸乙酯,残物加入石油醚搅拌析晶,过滤,80℃减压干燥,得中间体A6;所述A6为4-(2-乙酰氨基-4-氟-5-甲基苯基)丁酸;
A6反应式如下:
7)合成中间体A7:反应釜中加入二氯甲烷及中间体A6,冷却,于25℃内滴加氯化亚砜,完毕后在此温下反应0.4-0.6小时,再升温至30℃反应11小时,减压浓缩,残物在此加入等量的二氯甲烷,于3—6℃均分四次加入无水三氯化铝,间隔时间为10分钟,完毕后在同样的温度下搅拌反应1小时,升温于30℃反应24小时,取样反应结束后冷却于4-6℃加入定量5%盐酸,期间补充碎冰以控制温度,静止分相,酸相用氯仿萃取二次,合并有机相用饱和碳酸氢钠溶液洗涤二次,加入无水碳酸钾干燥,减压浓缩并回收溶剂,残物加入异丙醚搅拌析晶1小时,过滤,滤饼用异丙醚洗涤,50℃减压干燥,得中间体A7;所述A7为5-乙酰氨基-7-氟-8-甲基-1-四氢萘酮;
A7反应式如下:
8)合成中间体A8:反应釜中加入有机酸、A7及三乙基硅烷,于50℃反应4小时,取样反应结束后,减压浓缩有机酸,残物加入石油醚搅拌析晶,10℃过滤,滤饼用石油醚洗涤,50℃减压干燥,得中间体A8;所述A8为5-乙酰氨基-7-氟-8-甲基-1,2,3,4-四氢化萘;
A8反应式如下:
9)合成中间体A9:反应釜中加入丙酮、中间体A8和小苏打,在10-15℃于4小时内分批加入高锰酸钾,升温至室温反应1小时取样,反应结束后加入5%亚硫酸氢钠溶液消除未反应完的高锰酸钾;过滤,滤饼用预热至40—45℃的氯仿充分洗涤,减压浓缩滤液和洗涤液,残物再溶于氯仿,用饱和碳酸氢钠溶液洗涤三次,碳酸钾干燥,减压浓缩,残物加入乙醚搅拌析晶,10℃过滤,滤饼用乙醚洗涤,50℃减压干燥得中间体A9;所述A9为8-乙酰氨基-6-氟-5-甲基-1-四氢萘酮;
A9反应式如下:
10)合成中间体A10:反应釜中配有氮气导入装置,加入四氢呋喃和中间体A9,通氮待固体全溶后,于15℃滴加叔丁醇钾溶液,0.9-1.1小时加完,完毕后在相同的温度下反应0.5小时,在5—7℃滴加亚硝酸正丁酯,完毕后在相同温度下反应2小时,加水淬灭反应,用稀盐酸调节PH3-4,并充分搅拌0.5小时,过滤,滤饼水洗至中性,65℃减压干燥,得棕色A10中间体;所述A10为N,N'-(3-氟-4-甲基-8-氧代-5,6,7,8-四氢萘-1,7-二基)二乙酰胺;
A10反应式如下:
11)合成依喜替康中间体A11成品粗品:反应釜中,加入A10和20%盐酸,于58—60℃反应三小时,冷却至室温,加入水,搅拌15分钟,用铺设硅藻土的过滤装置过滤,滤液用670g水洗涤,合并滤液和洗涤液;反复多次用氯仿萃取,直至无产品萃出,浓缩残物加入乙醚析晶过滤,乙醚淋洗,干燥得成品粗品;所述A11为N-(8-氨基-6-氟-5-甲基-1-氧代-1,2,3,4-四氢萘-2-基)乙酰胺;
A11反应式如下:
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