CN114507163A - 一种制备2-氟-5-甲氧基苯磺酰氯的方法 - Google Patents
一种制备2-氟-5-甲氧基苯磺酰氯的方法 Download PDFInfo
- Publication number
- CN114507163A CN114507163A CN202011278152.XA CN202011278152A CN114507163A CN 114507163 A CN114507163 A CN 114507163A CN 202011278152 A CN202011278152 A CN 202011278152A CN 114507163 A CN114507163 A CN 114507163A
- Authority
- CN
- China
- Prior art keywords
- metal
- fluoro
- chloride
- methoxybenzenesulfonyl chloride
- preparing
- 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
- MEOZOFVLIUUROW-UHFFFAOYSA-N 2-fluoro-5-methoxybenzenesulfonyl chloride Chemical compound COC1=CC=C(F)C(S(Cl)(=O)=O)=C1 MEOZOFVLIUUROW-UHFFFAOYSA-N 0.000 title claims abstract description 20
- 238000000034 method Methods 0.000 title claims abstract description 8
- 229910052751 metal Inorganic materials 0.000 claims abstract description 24
- 239000002184 metal Substances 0.000 claims abstract description 24
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 9
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000002994 raw material Substances 0.000 claims abstract description 5
- 125000003118 aryl group Chemical group 0.000 claims abstract description 4
- 229910052744 lithium Inorganic materials 0.000 claims description 9
- 229910052749 magnesium Inorganic materials 0.000 claims description 9
- 239000011777 magnesium Substances 0.000 claims description 9
- -1 alkyl magnesium Chemical compound 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 6
- 229910052725 zinc Inorganic materials 0.000 claims description 5
- 239000011701 zinc Substances 0.000 claims description 5
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 4
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 3
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 3
- IPWBFGUBXWMIPR-UHFFFAOYSA-N 1-bromo-2-fluorobenzene Chemical compound FC1=CC=CC=C1Br IPWBFGUBXWMIPR-UHFFFAOYSA-N 0.000 claims 1
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 claims 1
- 150000004820 halides Chemical class 0.000 claims 1
- LYIGJBQYDRJPIR-UHFFFAOYSA-N 2-bromo-1-fluoro-4-methoxybenzene Chemical compound COC1=CC=C(F)C(Br)=C1 LYIGJBQYDRJPIR-UHFFFAOYSA-N 0.000 abstract description 7
- 238000009776 industrial production Methods 0.000 abstract description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 239000007788 liquid Substances 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 239000012295 chemical reaction liquid Substances 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 238000010791 quenching Methods 0.000 description 4
- 230000000171 quenching effect Effects 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- DBTNVRCCIDISMV-UHFFFAOYSA-L lithium;magnesium;propane;dichloride Chemical compound [Li+].[Mg+2].[Cl-].[Cl-].C[CH-]C DBTNVRCCIDISMV-UHFFFAOYSA-L 0.000 description 3
- 108010022404 serum-glucocorticoid regulated kinase Proteins 0.000 description 3
- LVKCSZQWLOVUGB-UHFFFAOYSA-M magnesium;propane;bromide Chemical compound [Mg+2].[Br-].C[CH-]C LVKCSZQWLOVUGB-UHFFFAOYSA-M 0.000 description 2
- 201000008482 osteoarthritis Diseases 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 102100040133 Free fatty acid receptor 2 Human genes 0.000 description 1
- 101000890668 Homo sapiens Free fatty acid receptor 2 Proteins 0.000 description 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
- BBPAICDPWINHGF-UHFFFAOYSA-N O=S(NC(C=C1)=CC=C1C1=CC=C(C=NN2)C2=C1)=O Chemical compound O=S(NC(C=C1)=CC=C1C1=CC=C(C=NN2)C2=C1)=O BBPAICDPWINHGF-UHFFFAOYSA-N 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- WXJBZPDYIKQTBZ-UHFFFAOYSA-L [Li+].[Cl-].[Br-].CC(C)[Mg+] Chemical compound [Li+].[Cl-].[Br-].CC(C)[Mg+] WXJBZPDYIKQTBZ-UHFFFAOYSA-L 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- BCEZZWURVXNNJM-UHFFFAOYSA-N n-[4-[3-amino-4-(2-methylpropoxy)-2h-pyrazolo[3,4-d]pyrimidin-6-yl]phenyl]-2-fluoro-5-methoxybenzenesulfonamide Chemical compound COC1=CC=C(F)C(S(=O)(=O)NC=2C=CC(=CC=2)C2=NC3=NNC(N)=C3C(OCC(C)C)=N2)=C1 BCEZZWURVXNNJM-UHFFFAOYSA-N 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/02—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/78—Halides of sulfonic acids
- C07C309/86—Halides of sulfonic acids having halosulfonyl groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C309/87—Halides of sulfonic acids having halosulfonyl groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing singly-bound oxygen atoms bound to the carbon skeleton
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
本发明公开了一种制备2‑氟‑5‑甲氧基苯磺酰氯的方法。以3‑溴‑4‑氟苯甲醚为原料，经与金属或金属试剂发生反应制得芳基金属试剂，再与磺酰氯反应制得2‑氟‑5‑甲氧基苯磺酰氯。本发明公开的方法反应步骤简短，操作简单，反应条件温和，适合于工业化生产。
Description
技术领域：
本发明属于药物化学领域，具体涉及一种制备2-氟-5-甲氧基苯磺酰氯的方法。
背景技术：
2-氟-5-甲氧基苯磺酰氯(CAS号：1214334-01-6)，结构如式I所示，是合成多种新药的重要中间体。
专利WO2014140065中公开一种新的化合物，N-(4-(氮杂吲哚-6-基)-苯基)-磺酰胺是有价值的药理学活性的化合物，其调节蛋白激酶活性，特别是血清和糖皮质激素调节激酶(SGK)的活性，是潜在的用于治疗SGK活性不适当疾病的药物，例如退化性关节疾病或炎性过程诸如骨关节炎或风湿病。其中，N-[4-(3-氨基-4-异丁氧基-1H-吡唑并[3,4-d]嘧啶-6-基)-苯基]-2-氟-5-甲氧基-苯磺酰胺；N-[4-(3-氨基-1H-吡唑并[3,4-d]嘧啶-6-基)-苯基]-2-氟-5-甲氧基-苯磺酰胺；N-{4-[4-(1-乙酰基-哌啶-4-基氧基)-3-甲基-1H-吡唑并[3,4-d]嘧啶-6-基]-苯基}-2-氟-5-甲氧基-苯磺酰胺等都是由2-氟-5-甲氧基苯磺酰氯作为原料制备而来。
专利WO2015198045中公开新化合物3-取代的2-胺基吲哚衍生物及类似物，其是潜在的治疗或预防与GPR43受体有关病症的药物，如糖尿病、肥胖症和炎症性肠病。其中，2-氟-5-甲氧基苯磺酰氯是合成相关化合物的重要原料，合成路线如Scheme 1所示。
目前，并无现有技术公开报道2-氟-5-甲氧基苯磺酰氯的制备方法。
发明内容：
本发明的目的在于针对现有技术的不足，提供一种操作简单易于产业化的2-氟-5-甲氧基苯磺酰氯的制备方法。
本发明采用的技术方案如下：
其中，X选自F、Cl、Br和I；M选自Mg、Zn、Li及其组合。
具体操作步骤为：以3-溴-4-氟苯甲醚为原料，经与金属或金属试剂发生反应制得芳基金属试剂III，再与磺酰氯反应制得2-氟-5-甲氧基苯磺酰氯。
进一步，所述金属或金属试剂选自C1-C6直链或支链烷基镁、C1-C6直链或支链烷基卤化镁卤化锂、C1-C6直链或支链烷基锂、金属镁、金属锌、金属锂中的一种或几种的混合物。
更进一步，所述金属或金属试剂选自金属镁、C1-C6直链或支链烷基镁、C1-C6直链或支链烷基卤化镁卤化锂。
更进一步，所述金属试剂选自异丙基氯化镁氯化锂、异丙基溴化镁氯化锂、异丙基氯化镁、异丙基溴化镁，优选异丙基氯化镁氯化锂。
本发明的有益效果在于，本发明公开了一种新的未见报道过的2-氟-5-甲氧基苯磺酰氯的制备方法，选用3-溴-4-氟苯甲醚为原料，反应步骤简短，操作简单，反应条件温和，适合于工业化生产。
附图说明
图1实施例1中2-氟-5-甲氧基苯磺酰氯的1HNMR图
具体实施方式
下面结合具体实施例对本发明的技术内容作进一步的阐述，其目的是为了更好的理解本发明的内容，但本发明的保护范围不限于此。
实施例1 2-氟-5-甲氧基苯磺酰氯的制备
将35mL异丙基氯化镁氯化锂加入50mL三颈瓶中，0℃下，加入6.0g 3-溴-4-氟苯甲醚搅拌反应1小时。将反应液降温至-30℃，并向其中加入溶于四氢呋喃中的磺酰氯，继续反应0.5小时，反应结束后，加水淬灭，继续搅拌0.5小时。旋转蒸掉四氢呋喃，用二氯甲烷萃取，水洗，旋转蒸发得到棕色液体，油泵蒸馏得到无色液体4.2g。1HNMR图见图1。
实施例2 2-氟-5-甲氧基苯磺酰氯的制备
将200mL异丙基溴化镁加入500mL三颈瓶中，0℃下，加入60g 3-溴-4-氟苯甲醚搅拌反应1小时。将反应液降温至-30℃，并向其中加入溶于四氢呋喃中的磺酰氯，继续反应0.5小时，反应结束后，加水淬灭，继续搅拌1小时。旋转蒸掉四氢呋喃，用二氯甲烷萃取，水洗，旋转蒸发得到棕色液体，油泵蒸馏得到无色液体38.1g。
实施例3 2-氟-5-甲氧基苯磺酰氯的制备
将3g金属锂加入500mL三颈瓶中，0℃下，加入5g 3-溴-4-氟苯甲醚搅拌反应4小时。将反应液降温至-45℃，并向其中加入溶于四氢呋喃中的磺酰氯，继续反应2小时，反应结束后，加水淬灭，继续搅拌1小时。旋转蒸掉四氢呋喃，用二氯甲烷萃取，水洗，旋转蒸发得到棕色液体，油泵蒸馏得到无色液体2.3g。
实施例4 2-氟-5-甲氧基苯磺酰氯的制备
将2g金属锌加入500mL三颈瓶中，0℃下，加入5g 3-溴-4-氟苯甲醚搅拌反应3小时。将反应液降温至-40℃，并向其中加入溶于四氢呋喃中的磺酰氯，继续反应1小时，反应结束后，加水淬灭，继续搅拌1小时。旋转蒸掉四氢呋喃，用二氯甲烷萃取，水洗，旋转蒸发得到棕色液体，油泵蒸馏得到无色液体1.7g。
Claims (2)
1.一种制备2-氟-5-甲氧基苯磺酰氯的方法，其特征在于，以3-溴-4-氟苯甲醚为原料，与金属或金属试剂发生反应制得芳基金属试剂III，再与磺酰氯反应制得2-氟-5-甲氧基苯磺酰氯。
具体路线如下：
其中，X选自F、Cl、Br和I；M选自Mg、Zn、Li及其组合。
2.一种如权利要求1所述的制备方法，其特征在于，所述金属或金属试剂选自C1-C6直链或支链烷基镁、C1-C6直链或支链烷基卤化镁卤化锂、C1-C6直链或支链烷基锂、金属镁、金属锌、金属锂中的一种或几种的混合物。
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011278152.XA CN114507163A (zh) | 2020-11-16 | 2020-11-16 | 一种制备2-氟-5-甲氧基苯磺酰氯的方法 |
| PCT/CN2021/114067 WO2022100195A1 (zh) | 2020-11-16 | 2021-08-23 | 一种制备2-氟-5-甲氧基苯磺酰氯的方法 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011278152.XA CN114507163A (zh) | 2020-11-16 | 2020-11-16 | 一种制备2-氟-5-甲氧基苯磺酰氯的方法 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN114507163A true CN114507163A (zh) | 2022-05-17 |
Family
ID=81546439
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202011278152.XA Pending CN114507163A (zh) | 2020-11-16 | 2020-11-16 | 一种制备2-氟-5-甲氧基苯磺酰氯的方法 |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN114507163A (zh) |
| WO (1) | WO2022100195A1 (zh) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103012407A (zh) * | 2011-09-27 | 2013-04-03 | 赛诺菲 | N-[4-(1H-吡唑并[3,4-b]吡嗪-6-基)-苯基]-磺酰胺类及其作为药物的用途 |
| CN109593802A (zh) * | 2018-12-24 | 2019-04-09 | 上海健康医学院 | 一种(r)-2-(2,5-二氟苯基)吡咯烷或其盐的制备方法 |
| CN109593803A (zh) * | 2018-12-24 | 2019-04-09 | 上海健康医学院 | (r)-2-(2,5-二氟苯基)吡咯烷或其盐的制备方法 |
| WO2020079205A1 (en) * | 2018-10-19 | 2020-04-23 | Les Laboratoires Servier | New amino-pyrimidonyl-piperidinyl derivatives, a process for their preparation and pharmaceutical compositions containing them |
| CN111647011A (zh) * | 2020-07-16 | 2020-09-11 | 宁夏中星显示材料有限公司 | 一种单卤代苯硼酸的制备方法 |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108003161B (zh) * | 2016-10-28 | 2020-10-09 | 正大天晴药业集团股份有限公司 | 神经营养因子酪氨酸激酶受体抑制剂 |
-
2020
- 2020-11-16 CN CN202011278152.XA patent/CN114507163A/zh active Pending
-
2021
- 2021-08-23 WO PCT/CN2021/114067 patent/WO2022100195A1/zh active Application Filing
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103012407A (zh) * | 2011-09-27 | 2013-04-03 | 赛诺菲 | N-[4-(1H-吡唑并[3,4-b]吡嗪-6-基)-苯基]-磺酰胺类及其作为药物的用途 |
| WO2020079205A1 (en) * | 2018-10-19 | 2020-04-23 | Les Laboratoires Servier | New amino-pyrimidonyl-piperidinyl derivatives, a process for their preparation and pharmaceutical compositions containing them |
| CN109593802A (zh) * | 2018-12-24 | 2019-04-09 | 上海健康医学院 | 一种(r)-2-(2,5-二氟苯基)吡咯烷或其盐的制备方法 |
| CN109593803A (zh) * | 2018-12-24 | 2019-04-09 | 上海健康医学院 | (r)-2-(2,5-二氟苯基)吡咯烷或其盐的制备方法 |
| CN111647011A (zh) * | 2020-07-16 | 2020-09-11 | 宁夏中星显示材料有限公司 | 一种单卤代苯硼酸的制备方法 |
Non-Patent Citations (1)
| Title |
|---|
| BHATTACHARYA等: "Preparation of Arenesulphonyl Chlorides from Grignard Reagents" * |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2022100195A1 (zh) | 2022-05-19 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA1087205A (en) | 2-amino-3-(5-and 6-)benzoylphenylacetic acids, esters and metal salts thereof | |
| CA3082115A1 (en) | Process for preparing tapinarof | |
| US7091364B2 (en) | Process for the industrial synthesis of tetraesters of 5-[bis(carboxymethyl)amino]-3-carboxymethyl-4-cyano-2-thiophenecarboxylic acid, and application to the synthesis of bivalent salts of ranelic acid and their hydrates | |
| AU606621B2 (en) | Azaindole and indolizine derivatives, processes for their production and their use as pharmaceuticals | |
| US3120551A (en) | 5-(4-biphenylyl)-3-methylvaleric acid and functional derivatives thereof | |
| US4029816A (en) | Substituted 2-aminomethyl-6-iodophenols | |
| TW202000643A (zh) | 製備一氧化氮供體型前列腺素類似物之方法 | |
| EP0053021A2 (en) | Process for 5-aroylation of 1,2-dihydro-3H-pyrrolo(1,2-a)pyrrole-1-carboxylic esters and nitriles | |
| US8153826B2 (en) | Process for production of (±)-3a,6,6,9a-Tetramethyldecahydronaphtho[2,1-b]Furan-2(1H)-one | |
| JP2000063334A (ja) | エンイン誘導体の新規製造中間体及びその製造法 | |
| EP0011654A1 (en) | Nuclear substituted 2-hydroxymethane-sulfamic acids and pharmaceutical compositions | |
| EP0000200A1 (en) | New N-amidino-3,5-diamino-6-substituted-2-pyrazinecarboxamides and process for preparing same | |
| CN114507163A (zh) | 一种制备2-氟-5-甲氧基苯磺酰氯的方法 | |
| JPS62123180A (ja) | ｐ−アミノフエノ−ル誘導体 | |
| JPS59225151A (ja) | １，２−ジフエニル−１−〔４−（２−ジメチルアミノエトキシ）フエニル〕−１−ブテンのＥ異性体をタモキシフエンＨＣｌに転化させる方法 | |
| EP0010787B1 (en) | Isomerisation of 3-azabicyclo(3.1.0)hexane derivatives | |
| EP0026675B1 (en) | 1-azaxanthone-3-carboxylic acids, their preparation and pharmaceutical compositions containing them | |
| Hammond et al. | New synthesis of 1-azabicyclo [5.3. 0] decane | |
| JPH09169733A (ja) | ４−トリフルオロメチルニコチン酸の製造方法 | |
| JPS5857419B2 (ja) | １−シクロプロピル−１−フエニル−ω−アミノ−１−低級アルカノイルオキシアルカン類の製造方法 | |
| JP2003517029A (ja) | トリフルオロメチルアセトフェノンの製造方法 | |
| KR100195888B1 (ko) | 디엘-3-메칠-시크로펜타데칸-1-온의 제조방법 | |
| TW201329033A (zh) | ３－烴基－３－甲基丁酸或其鈣鹽之製備方法 | |
| Haynes | The Synthesis of 1, 2, 3, Triphenylpropane | |
| JP2558275B2 (ja) | ゲラニルフエニルスルホンの製造方法 |
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 | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20220517 |