CN114891004A - 一种西格列汀中间体化合物的制备方法 - Google Patents
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- 238000006482 condensation reaction Methods 0.000 claims abstract description 20
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- 238000006243 chemical reaction Methods 0.000 claims description 16
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- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- MFFMDFFZMYYVKS-SECBINFHSA-N sitagliptin Chemical compound C([C@H](CC(=O)N1CC=2N(C(=NN=2)C(F)(F)F)CC1)N)C1=CC(F)=C(F)C=C1F MFFMDFFZMYYVKS-SECBINFHSA-N 0.000 description 13
- 229960004034 sitagliptin Drugs 0.000 description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
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- 239000003153 chemical reaction reagent Substances 0.000 description 9
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- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 6
- 238000003756 stirring Methods 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
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- 239000007787 solid Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 description 3
- 101000930822 Giardia intestinalis Dipeptidyl-peptidase 4 Proteins 0.000 description 3
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 150000001576 beta-amino acids Chemical class 0.000 description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
- WJPYOCIWVYDFDT-UHFFFAOYSA-N ethyl 3-oxo-4-(2,4,5-trifluorophenyl)butanoate Chemical compound CCOC(=O)CC(=O)CC1=CC(F)=C(F)C=C1F WJPYOCIWVYDFDT-UHFFFAOYSA-N 0.000 description 3
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
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- 238000010992 reflux Methods 0.000 description 3
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- 208000013016 Hypoglycemia Diseases 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 231100000024 genotoxic Toxicity 0.000 description 1
- 230000001738 genotoxic effect Effects 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 235000003642 hunger Nutrition 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000003914 insulin secretion Effects 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 229940090473 januvia Drugs 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- TWHXWYVOWJCXSI-UHFFFAOYSA-N phosphoric acid;hydrate Chemical compound O.OP(O)(O)=O TWHXWYVOWJCXSI-UHFFFAOYSA-N 0.000 description 1
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- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
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- 238000010189 synthetic method Methods 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- 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
Abstract
本发明涉及医药合成领域,涉及一种西格列汀中间体化合物的制备方法。该中间体化合物经活化、缩合反应制备得到。本发明缩合反应收率高,适合工业化生产。
Description
技术领域
本申请是申请号为201810445766.9、申请日为2018.05.11的中国发明专利《一种西格列汀中间体的制备方法》的分案申请,本发明涉及医药合成领域,涉及一种西格列汀中间体化合物的制备方法。
背景技术
西格列汀(Sitagliptin),结构式如下:
化学名为(2R)-4-氧代-4-[3-三氟甲基-5,6-二氢[1,2,4]三唑[4,3-α]吡嗪-7(8H)-基]-1-(2,4,5-三氟苯基)-丁-2-胺,是美国Merck公司研发的二肽基肽酶-IV(DPP-IV)抑制剂。2006年10月,其磷酸盐一水合物(商品名Januvia)作为首个DPP-IV抑制剂被美国FDA批准上市,临床用于治疗II型糖尿病。西格列汀的作用特点是在刺激胰岛素分泌的同时,能减轻饥饿感,而且不会使体重增加,也不会发生低血糖和水肿现象。
目前报道的合成方法有以下几种:
1、采用1-羟基苯并三唑(HOBt)/1-乙基-(3-二甲基氨基丙基)碳酰二亚胺(E DC)进行β-氨基酸和环胺进行缩合反应得到酰胺,然后脱保护,得到最终产物西格列汀。该路线所用试剂较为昂贵,中间产物精制较困难,不太适宜工业化生产(Kim,D.etal,J.Med.Chem.,2005,48,p141-151;Kowalchick,J.E.et al,J.Med.Chem.Lett.,2007,17,5934-5939),
2、Hansen等人同样利用1-羟基苯并三唑(HOBt)/1-乙基-(3-二甲基氨基丙基)碳酰二亚胺(EDC)为缩合剂,进行β-氨基酸和胺进行缩合反应得到酰胺,然后钯催化氢化脱保护,得到最终产物西格列汀。该路线使用试剂价格也比较昂贵,最终产品有重金属残留问题(Hansen,K.B.et al,Organic Process Research&De velopment,2005,9,634-639),
3、CN104693207(安润医药科技)使用氯磺酰酯作为活化试剂,
化合物(2)与化合物(10)在有机溶剂中,在碱存在的条件下在-10~50℃下反应制备得到混合酸酐中间体(11)的溶液;将化合物(3)添加到上述混合酸酐中间体(10)的溶液中,然后在-10~50℃下反应得到化合物(4);制备得到的化合物(4)在酸的作用下发生脱保护反应,得到化合物(1),即西格列汀。路线中使用氯磺酰酯为活化试剂,收率低,且氯磺酰酯为潜在基因毒杂质,严重影响用药安全性。
为克服现有技术中的上述问题,本发明提供了一种西格列汀的合成方法,该方法收率高,适合于工业化生产。
发明内容
本发明制备西格列汀的方法涉及缩合反应步骤,该步骤中加入了活化试剂,反应收率高,适合于工业化生产。
为实现本发明的技术目的,本发明提供了如下的技术方案:
首先,本发明提供了一种式c化合物,结构式如下:
其中,L为羰基,氨基或氨基保护基,R2为氢或C1-8烷基,R1是取代苄基,苄基的苯环上被三个氟取代。较优选地,本发明提供的式c化合物具体结构式如下:
本发明进一步提供了一种西格列汀中间体式d化合物的制备方法,由式b化合物在活化试剂的作用下经活化后与式a化合物经缩合反应制备,
其中,L为羰基,氨基或氨基保护基,R1是取代苄基,苄基的苯环上被三个氟取代,R2是氢或C1-8烷基。
所述缩合反应中的活化试剂为氯甲酸乙酯或草酰氯。
所述缩合反应中的活化试剂与式b化合物的摩尔比为0.5~2:1;较优选地为0.9~1.0:1。
进一步地,该西格列汀中间体化合物的制备方法,由酮酸化合物经活化、缩合反应制备,反应方程式为:
所述活化,缩合反应的温度为10℃~40℃。
或者由式c-1化合物经活化、缩合反应制备,反应方程式为:
其中,L1选择性为氨基或氨基保护基。
所述活化,缩合反应的温度为-10℃以下;较优选地,为-25℃~-15℃。
本发明进一步提供了一种西格列汀的制备方法,由β-氨基酸化合物经活化、缩合反应和脱保护基反应制备,
本发明第三方面提供了胺化合物或β-酮酯化合物与式a化合物经缩合反应制备β-氨基酸衍生物或二羰基化合物的方法,
其中,L为羰基,氨基或氨基保护基;R1是取代苄基,苄基的苯环上被三个氟取代,R2是C1-8烷基。
所述活化试剂为氯甲酸乙酯或草酰氯。
本发明提供的西格列汀中间体的制备方法,由酮酸化合物经缩合反应,胺化反应制备,反应方程式为:
本发明提供的西格列汀的制备方法,由缩合反应和选择性脱保护基反应制备,反应方程式为:
L1选择性地为氨基或氨基保护基。
本发明提供西格列汀的制备方法,缩合反应步骤收率高,是一条具备工业化应用前景的路线,适宜于商业化生产。
具体实施方式
为了进一步理解本发明,下面结合实施例对本发明提供的一种西格列汀中间体的制备方法进行详细说明。需要理解的是,这些实施例描述只是为进一步详细说明本发明的特征,而不是对本发明范围或本发明权利要求范围的限制。
实施例1:活化缩合反应
化合物a(5.6g,24.5mmol)和N,N-二异丙基乙胺(7.0g,54.2mmol)加入到二氯甲烷(90mL)中,20~25℃搅拌1小时,备用。
250ml三口烧瓶中加入β-氨基酸化合物(7.3g,21.9mmol)、N,N-二异丙基乙胺(7.0g,54.2mmol)和二氯甲烷(100mL),20~25℃搅拌。氮气保护下降温至-25~-20℃,滴加氯甲酸乙酯(2.6g,24.0mmol)。滴加完成后,继续在-25~-20℃反应。反应完全,得活化后的产物的二氯甲烷溶液。氮气保护下,于-20~-15℃滴加式a化合物的二氯甲烷溶液,滴加完成后,继续在-25~-20℃反应。
反应完成后,反应混合物中加入水,搅拌。分层,取下层有机相,弃上层水相。有机相用饱和硫酸氢钠水溶液洗涤后,无水硫酸钠干燥。过滤,滤液减压浓缩至干,残余物中加入乙酸乙酯,升温至回流。降温结晶。降温至20~25℃,抽滤,滤饼用乙酸乙酯淋洗后,60~65℃常压烘干,得目标产物白色固体(10.1g,19.9mmol),摩尔收率90.9%。
1H NMR(400MHz,CDCl3)1.36(s,9H),2.63~2.76(m,2H),2.83~2.97(m,2H),4.09~4.24(m,4H),5.00~5.16(m,2H),5.29(s,1H),6.83~6.91(m,1H),7.04~7.10(m,1H)。
实施例2:
100ml四口烧瓶中加入化合物Boc保护的化合物(5.0g,9.85mmol)和异丙醇(50mL),搅拌溶解。滴入30%盐酸异丙醇(2.4g,54.2mmol)溶液。滴加完成后,升温。反应完成后,滴加氢氧化钠水溶液,调节pH。减压浓缩反应液。残余物中加入异丙醇,搅拌。过滤,滤饼用异丙醇淋洗。滤液中滴加80%磷酸,滴加完成后,升温,保温反应。降温,抽滤,滤饼用异丙醇淋洗后,烘干,得白色固体(4.5g,8.6mmol),即化合物西格列汀磷酸盐一水合物,摩尔收率87.9%。
实施例3:
250ml三口瓶中加入二氯甲烷(100ml)和酮酸化合物(10.0g,43.07mmol),搅拌溶解。于10~15℃滴加草酰氯(6.56g,51.68mmol),滴加完成,升温至30~35℃搅拌反应。反应完全,于30~40℃减压浓缩至干得淡黄色液体(10.91g,43.64mmol),250ml三口烧瓶中加入二氯甲烷(100ml),三乙胺(5.79g,57.24mmol)和上述淡黄色液体(10.0g,52.04mmol),搅拌溶解。降温至0~5℃滴加式a化合物的游离碱(13.0g,52.04mmol)/二氯甲烷(20ml)溶液,滴加完成后升温至10~15℃搅拌反应。反应完成,加入水,搅拌。分层,取下层有机相,弃上层水相。有机相加入5%氯化钠水溶液洗涤后于30~40℃减压浓缩至干,得类白色固体(19.24g,47.36mmol),即酮酰胺化合物,摩尔收率91%。
实施例4:
500ml三口烧瓶中加入甲苯(300ml),酮酰胺化合物(19.24g,47.36mmol)和醋酸胺(50.0g),搅拌溶解。装上分水器,升温至回流。回流保温。减压浓缩物料至干。残余物中加入乙酸乙酯和水,搅拌。分层,取上层有机相,弃下层水相。有机相减压浓缩至干,得淡黄色固体(18.47g,45.57mmol),即烯胺化合物,摩尔收率96.2%。
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