CN116854674A - 盐酸特拉唑嗪的制备方法及其中间体 - Google Patents
盐酸特拉唑嗪的制备方法及其中间体 Download PDFInfo
- Publication number
- CN116854674A CN116854674A CN202310796585.1A CN202310796585A CN116854674A CN 116854674 A CN116854674 A CN 116854674A CN 202310796585 A CN202310796585 A CN 202310796585A CN 116854674 A CN116854674 A CN 116854674A
- Authority
- CN
- China
- Prior art keywords
- preparation
- reaction
- acid
- carried out
- terazosin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- VCKUSRYTPJJLNI-UHFFFAOYSA-N terazosin Chemical compound N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(CC1)CCN1C(=O)C1CCCO1 VCKUSRYTPJJLNI-UHFFFAOYSA-N 0.000 title claims abstract description 35
- 229960001909 terazosin hydrochloride Drugs 0.000 title claims abstract description 27
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- -1 tetrahydrofurfuryl Chemical group 0.000 claims abstract description 14
- HJVAVGOPTDJYOJ-UHFFFAOYSA-N 2-amino-4,5-dimethoxybenzoic acid Chemical compound COC1=CC(N)=C(C(O)=O)C=C1OC HJVAVGOPTDJYOJ-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000002253 acid Substances 0.000 claims abstract description 11
- 238000005660 chlorination reaction Methods 0.000 claims abstract description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 27
- 238000006243 chemical reaction Methods 0.000 claims description 24
- 238000003756 stirring Methods 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- 229960001693 terazosin Drugs 0.000 claims description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 7
- 238000001816 cooling Methods 0.000 claims description 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 3
- 239000003651 drinking water Substances 0.000 claims description 3
- 235000020188 drinking water Nutrition 0.000 claims description 3
- 239000012467 final product Substances 0.000 claims description 3
- 238000000967 suction filtration Methods 0.000 claims description 2
- 238000004821 distillation Methods 0.000 claims 1
- 238000010438 heat treatment Methods 0.000 claims 1
- 239000000203 mixture Substances 0.000 claims 1
- 238000004321 preservation Methods 0.000 claims 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 abstract description 8
- 239000003814 drug Substances 0.000 abstract description 5
- DJDBLBBSUAQYAA-UHFFFAOYSA-N piperazine-1-carbonitrile Chemical compound N#CN1CCNCC1 DJDBLBBSUAQYAA-UHFFFAOYSA-N 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 2
- 230000020477 pH reduction Effects 0.000 abstract 1
- 238000003786 synthesis reaction Methods 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 description 24
- 238000000034 method Methods 0.000 description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 150000001875 compounds Chemical class 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 229940125782 compound 2 Drugs 0.000 description 6
- 239000012535 impurity Substances 0.000 description 5
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 238000009776 industrial production Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000001308 synthesis method Methods 0.000 description 4
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 description 3
- 208000004403 Prostatic Hyperplasia Diseases 0.000 description 3
- 238000007664 blowing Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000010189 synthetic method Methods 0.000 description 3
- DGHKCBSVAZXEPP-UHFFFAOYSA-N 2,4-dichloro-6,7-dimethoxyquinazoline Chemical compound ClC1=NC(Cl)=C2C=C(OC)C(OC)=CC2=N1 DGHKCBSVAZXEPP-UHFFFAOYSA-N 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- WJUFSDZVCOTFON-UHFFFAOYSA-N veratraldehyde Chemical compound COC1=CC=C(C=O)C=C1OC WJUFSDZVCOTFON-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- DBOAGRILJPETJN-UHFFFAOYSA-N 2-chloro-6,7-dimethoxy-1h-quinazolin-4-one Chemical compound N1=C(Cl)NC(=O)C2=C1C=C(OC)C(OC)=C2 DBOAGRILJPETJN-UHFFFAOYSA-N 0.000 description 1
- KWNQIIMVPSMYEM-UHFFFAOYSA-N 6,7-dimethoxy-1h-quinazoline-2,4-dione Chemical compound N1C(=O)NC(=O)C2=C1C=C(OC)C(OC)=C2 KWNQIIMVPSMYEM-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229940127088 antihypertensive drug Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000006396 nitration reaction Methods 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000036513 peripheral conductance Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 239000003087 receptor blocking agent Substances 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- ZVCDLGYNFYZZOK-UHFFFAOYSA-M sodium cyanate Chemical compound [Na]OC#N ZVCDLGYNFYZZOK-UHFFFAOYSA-M 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- NZMOFYDMGFQZLS-UHFFFAOYSA-N terazosin hydrochloride dihydrate Chemical compound [H+].O.O.[Cl-].N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(CC1)CCN1C(=O)C1CCCO1 NZMOFYDMGFQZLS-UHFFFAOYSA-N 0.000 description 1
- HFFLGKNGCAIQMO-UHFFFAOYSA-N trichloroacetaldehyde Chemical compound ClC(Cl)(Cl)C=O HFFLGKNGCAIQMO-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 238000004065 wastewater treatment Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members 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
- C07D307/20—Oxygen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明公开了一种盐酸特拉唑嗪的制备新方法,属于药物合成领域。本发明先将氰基哌嗪和四氢糠酸缩合后,再与6‑氨基藜芦酸构建喹唑啉环,氯化,氨化和酸化最后得到盐酸特拉唑嗪,通过本发明极大地降低了工艺杂质,减少了精制的次数,提高了产品的纯度和收率,更适合工业化生产。
Description
技术领域
本发明属于医药化工领域,涉及治疗高血压和良性***增生药物盐酸特拉唑嗪制备方法及其中间体。
背景技术
盐酸特拉唑嗪(Terazosin)作为新型长效选择性α1-去甲肾上腺受体阻滞剂,能降低外周血管阻力,是一种新型长效抗高血压和治疗良性***增生症的药物。其在美国、欧洲及日本等发达国家和地区已获得广泛临床应用,同时也是国际BPH咨询委员会推荐用于治疗***增生症的一线药物。目前,盐酸特拉唑嗪已被列入我国基本药物目录,国家公费医疗报销品种。近年来,盐酸特拉唑嗪制剂市场销售额增长快速,原料药需求不断增大,具有广阔的市场前景。为满足盐酸特拉唑嗪原料药的市场需求,保障供应,对盐酸特拉唑嗪关键中间体的工艺研究具有重要社会经济价值,极具市场前景。
盐酸特拉唑嗪化学名为1-(4-氨基-6,7-二甲氧基-2-喹唑啉基)-4-[(四氢呋喃基)碳酰基]哌嗪盐酸盐二水合物,它的结构式为
专利US6015819报道一种盐酸特拉唑嗪的合成方法。该路线以藜芦醛为原料,经硝化、氧化、还原后得到2-氨基-4,5-二甲氧基苯甲酸,再环合得到2,4-二羟基-6,7-二甲氧基喹唑啉,然后经过氯取代、氨化得到4-氨基-2-氯-6,7-二甲氧基喹唑啉,再与无水哌嗪和四氢糠酸反应生成特拉唑嗪,最后成盐得到盐酸特拉唑嗪,具体合成路线如下所示。
该路线合成步骤较长,总收率不足20%。合成喹唑啉环收率较低,低于55%,且反应温度高,使用氰酸钠作为试剂,废水处理等安全环保问题突出。另外,在工艺条件下,2,4-二氯-6,7-二甲氧基喹唑啉不稳定,非常容易水解,导致工作操作难度系数高、产品质量不可控,限制了该工艺的工业化应用。
专利(CN108358828)报道一种盐酸特拉唑嗪的合成方法,该方法在专利US6015819的路线基础上进行改进,通过三氯乙醛、盐酸羟胺获得氨基和羧基的方法,得到6-氨基藜芦酸,后续反应步骤完全一致,路线如下所示。
此合成路线仅是改进了6-氨基藜芦酸的合成方法,对盐酸特拉唑嗪的母核喹唑啉环的改进不大。
总体说来,现有工艺均是先构建喹唑啉环,然后进行氯化、氨化后,再依次与哌嗪、四氢糠酸缩合得到盐酸特拉唑嗪,存在以下问题:
1)该工艺方法的中间体2,4-二氯-6,7-二甲氧基喹唑啉不稳定,其它中间体也极易生成杂质。这些杂质均具有喹唑啉环结构,非常类似特拉唑嗪,且产生在原料药生产的后期步骤,去除非常困难,因此产品需要多次精制才能符合药典要求,导致产品收率低下,生产率也不高。
2)4-氨基-6,7-二甲基-2-哌嗪基-4-喹唑啉分子结构中存在两个可以被酰化的氮原子,所以反应选择性不高,使得产品杂质多,分离困难,收率低,质量难以控制。
3)现有工艺步骤均较长,工业化生产操作难度较大,三废处理困难,关键反应收率偏低,路线成本仍然偏高,所以仍需要找到工艺路线简单、成本低廉、适宜工业化生产的方法合成盐酸特拉唑嗪。
发明内容
发明目的:为解决上述技术问题,本发明提供一种中间体稳定、步骤简短、收率高的盐酸特拉唑嗪的制备方法。
为实现发明目的,本发明目的之一提供了一种用于制备盐酸特拉唑嗪的中间体化合物2及其合成方法,化合物2结构式如下:
盐酸特拉唑嗪的中间体化合物2的合成方法是将中间体式1与四氢糠酸反应得到化合物式2。
本发明目的之二是提供了一种用于制备盐酸特拉唑嗪的中间体化合物4及其合成方法,化合物4结构式如下:
盐酸特拉唑嗪中间体化合物4的合成方法,包括将中间体式2与6-氨基藜芦酸环合后,再经过氯化反应得到化合物式4。
本发明关于盐酸特拉唑嗪的制备是通过先将氰基哌嗪与四氢糠酸缩合后,再构建喹唑啉环,极大的提高了喹唑啉环的稳定性,工艺杂质大幅度减少,中间体及成品精制次数减少,提高了反应收率。并且通过构建新中间体化合物2和化合物4,对实验条件进行了优化,提高了每步反应的收率和中间体的分离纯度。这些改进都极大地提高了路线效率,进一步降低了工艺成本,减少了副产物的生成并利于最终成品纯度的提高。该工艺路线步骤减少、操作简单,不仅收率较高,得到的产品纯度也较高,更适合工业化生产,反应路线如下所示:
第一步:中间体1与四氢糠酸生成中间体2;
第二步:中间体2与6-氨基藜芦酸环合后得到中间体3;
第三步:中间体3在经过氯化得到中间体4;
第四步:中间体4氨化后得到特拉唑嗪,在经过盐酸酸化得到终产品。
有益效果:本发明提供了一种盐酸特拉唑嗪的制备方法,相比现有技术具有以下优点:合环方式的改变提高了喹唑啉环的稳定性,工艺杂质大大减少,该制备方法的中间体易于纯化,反应条件温和,后处理操作简便,总收率可达到35%以上,更适合大规模工业化生产。
具体实施方式
以下对本发明的原理和特征进行描述,所举实施实例用于进一步解释本发明,但不限制本发明的范围。
实施例1 4-(四氢呋喃 -2-羰基)哌嗪 -1-碳腈(化合物2)
将氰基哌嗪(55.57g,0.50mol)加入到甲苯(277.87g)中,升温至40-50℃, 滴加2-四氢糠酸甲苯溶液(58.02g,0.50mol,溶于55.57g甲苯中),用时1.0-2.0h,滴毕,升温至回流(115~120℃)反应5.5h。反应完毕,减压蒸出甲苯,至无馏出液,产品为淡黄色至棕色油状物。收率83.2%,纯度(GC)≥98.5%。
实施例2 1-(4-羟基-6,7-二甲氧基-2-喹唑啉基)-4-[(四氢呋喃基)碳酰基]哌嗪(化合物3)
将4-(四氢呋喃 -2-羰基)哌嗪 -1-碳腈(115.02g,0.55mol),6-氨基藜芦酸(98.59g,0.50mol),甲苯(266.19g),饮用水(29.58g),NaOH(20.00g,0.50mol)加入到1L高压反应釜中,关闭反应釜,升温至140-160℃搅拌反应6h。反应完毕,料液降温转移至1L反应瓶中,冷却析晶,过滤。滤饼置80℃鼓风干燥得类白色固体,收率:86.9%,纯度(HPLC)≥99.0%。
实施例3 1-(4-氯-6,7-二甲氧基-2-喹唑啉基)-4-[(四氢呋喃基)碳酰基]哌嗪(化合物4)
将化合物3(194.08g,0.50mol),三氯氧磷(579ml),DMF(32.00g) 投入到2L反应瓶中,加热,控温90-100℃反应10h。反应完毕,减压蒸馏出多余的三氯氧磷,然后向剩余物中滴加冰水(400.00g),二氯甲烷萃取2次,每次用二氯甲烷600ml。合并二氯甲烷相,减压蒸馏出二氯甲烷,剩余物中加入甲苯(610.29g),冷却析晶。过滤,滤饼鼓风干燥得类白色粉末,收率:87.2%,纯度(HPLC)≥99.0%。
实施例4 特拉唑嗪
将2-氯-4-羟基-6,7-二甲氧基喹唑啉(203.43g,0.50mol),DMF(1017.15g)加入2L反应瓶中搅拌,待固体全部溶解后,于室温下通氨气8h,停止通氨气后继续搅拌反应2h。减压蒸馏DMF,蒸出约一半量的DMF,冰浴冷却下加入冰水(1017.15g),析出固体。过滤,用冰水洗涤滤饼两次,鼓风干燥得淡黄色结晶183.92g,收率:95.1%,纯度(HPLC)≥99.0%。
实施例5 盐酸特拉唑嗪
将特拉唑嗪(69.7 1g,0.18 mol),无水乙醇(766.70g),纯化水(83.00g),加入反应瓶中,搅拌加热至70- 75℃,滴加6M盐酸,调pH至2.49,加毕,保温搅拌0.5h,降温至40-50℃,搅拌1h,再降温至0~5℃,保温搅拌2h后抽滤,鼓风烘干得白色固体,收率93.8%,纯度(HPLC)≥99.5%)。
Claims (7)
1.一种盐酸特拉唑嗪的制备方法,其特征在于包括以下步骤:
第一步:中间体1与四氢糠酸生成中间体2;
第二步:中间体2与6-氨基藜芦酸环合后得到中间体3;
第三步:中间体3在经过氯化得到中间体4;
第四步:中间体4氨化后得到特拉唑嗪,在经过盐酸酸化得到终产品
2.根据权利要求1所述的的制备方法,其特征在于第一步将2-四氢糠酸的甲苯溶液滴加到含有中间体1和甲苯的反应瓶中,升温回流反应。
3.根据权利要求1所述的的制备方法,其特征在于第二步将中间体2、6-氨基藜芦酸、甲苯、饮用水和氢氧化钠加入到反应釜,升温至140-160℃反应。
4.根据权利要求1所述的的制备方法,其特征在于第三步将中间体3、三氯氧磷和DMF加入到反应瓶中,回流反应。
5.根据权利要求1所述的的制备方法,其特征在于第四步将中间体4于DMF中溶解,室温下通入氨气搅拌反应得到特拉唑嗪,再将中间体5、乙醇和饮用水加入到反应瓶中,搅拌加热70-75℃,滴加盐酸调pH至2.49左右,搅拌降温40-50℃,搅拌再降温0-5℃,保温搅拌,抽滤。
6.根据权利要求2所述的制备方法,其特征在于中间体1与2-四氢糠酸的投料量比为1:1,升温回流反应5.5h,结束后减压蒸馏。
7.根据权利要求3所述的制备方法,其特征在于加入的中间体2、6-氨基藜芦酸和氢氧化钠投料量比为1-1.1:1:1-1.2。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202310796585.1A CN116854674A (zh) | 2023-07-03 | 2023-07-03 | 盐酸特拉唑嗪的制备方法及其中间体 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202310796585.1A CN116854674A (zh) | 2023-07-03 | 2023-07-03 | 盐酸特拉唑嗪的制备方法及其中间体 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN116854674A true CN116854674A (zh) | 2023-10-10 |
Family
ID=88233368
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202310796585.1A Pending CN116854674A (zh) | 2023-07-03 | 2023-07-03 | 盐酸特拉唑嗪的制备方法及其中间体 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN116854674A (zh) |
-
2023
- 2023-07-03 CN CN202310796585.1A patent/CN116854674A/zh active Pending
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN109020881B (zh) | 一种阿帕替尼的制备方法 | |
IL167209A (en) | Process for the preparation of 4- (3'-chloro-4'-fluoroanilino) -7-methoxy-6- (3-morpholinopropoxy) quinazoline and its intermediates as new compounds | |
WO2013026391A1 (zh) | 嘧菌酯及其合成中专用中间体的合成方法 | |
CN101735157B (zh) | 一种盐酸埃罗替尼的制备方法 | |
NZ580382A (en) | Process for the preparation of gefitinib | |
CN111333658A (zh) | 一种培美曲塞二钠水合物的制备方法 | |
CN107935997B (zh) | 一种奥斯替尼的合成方法 | |
CN101351459A (zh) | 4(3h)-喹唑啉酮衍生物的制造方法 | |
CN116854674A (zh) | 盐酸特拉唑嗪的制备方法及其中间体 | |
CN113336703B (zh) | 1,3,4,5-四取代1h-吡唑衍生物的合成 | |
CN110590601B (zh) | 一种丙二腈的合成方法 | |
CN109206377B (zh) | 一种制备n-(3-氯-4-氟苯基)-7-氟-6-硝基-4-喹唑啉胺的新方法 | |
CN101555248B (zh) | 一种多取代1,5-萘啶化合物的制备方法 | |
CN114349711B (zh) | 一种(R)-1-Boc-3-羟甲基哌嗪的合成方法 | |
CN109810052A (zh) | 一种高选择性的阿帕替尼的简便制备方法 | |
CN101759653B (zh) | 6,7-二甲氧基喹唑啉-4-酮的制备方法 | |
CN102532125A (zh) | 一种氨曲南化合物的合成方法 | |
CN110204490B (zh) | 一种二取代4-氯喹啉-3-甲腈衍生物及伯舒替尼的制备方法 | |
CN117430605A (zh) | 一种kras g12c抑制剂amg-510中间体的合成方法 | |
AU781221B2 (en) | Novel synthesis and crystallization of piperazine ring-containing compounds | |
CN116789672A (zh) | 一种氟马西尼的生产工艺 | |
CN116768901A (zh) | 一种培美曲塞二钠的制备方法 | |
CN117247360A (zh) | 一种2-甲氧基-3-(1-甲基-1h-1,2,4-***-3-基)苯胺的制备方法 | |
CN116283803A (zh) | 一种氟马西尼中间体的制备方法 | |
CN114716378A (zh) | 一种1,3,4-三取代-5-氰基吡唑衍生物的合成方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination |