CN1871210A - 制备α－(3－芳硫基)－苯乙酮的方法 - Google Patents
制备α－(3－芳硫基)－苯乙酮的方法 Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 45
- 125000001424 substituent group Chemical group 0.000 claims abstract description 16
- 150000007944 thiolates Chemical class 0.000 claims abstract description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 8
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 5
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 16
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 claims description 14
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 claims description 10
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 6
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 125000004646 sulfenyl group Chemical group S(*)* 0.000 claims description 5
- 229910052728 basic metal Inorganic materials 0.000 claims description 3
- 150000003818 basic metals Chemical class 0.000 claims description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 125000005110 aryl thio group Chemical group 0.000 claims 1
- -1 C1-C6-alkyl radical Chemical class 0.000 abstract description 5
- 229910052783 alkali metal Inorganic materials 0.000 abstract description 3
- 150000001340 alkali metals Chemical class 0.000 abstract description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 1
- SLRMQYXOBQWXCR-UHFFFAOYSA-N 2154-56-5 Chemical compound [CH2]C1=CC=CC=C1 SLRMQYXOBQWXCR-UHFFFAOYSA-N 0.000 abstract 1
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- 150000001875 compounds Chemical class 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- LIGACIXOYTUXAW-UHFFFAOYSA-N phenacyl bromide Chemical compound BrCC(=O)C1=CC=CC=C1 LIGACIXOYTUXAW-UHFFFAOYSA-N 0.000 description 4
- IMACFCSSMIZSPP-UHFFFAOYSA-N phenacyl chloride Chemical compound ClCC(=O)C1=CC=CC=C1 IMACFCSSMIZSPP-UHFFFAOYSA-N 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- QMVAZEHZOPDGHA-UHFFFAOYSA-N 3-methoxybenzenethiol Chemical compound COC1=CC=CC(S)=C1 QMVAZEHZOPDGHA-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 125000005103 alkyl silyl group Chemical group 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 230000005595 deprotonation Effects 0.000 description 2
- 238000010537 deprotonation reaction Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- AHSPHTNFUZYFCW-UHFFFAOYSA-N 2-(chloromethoxy)-1-phenylethanone Chemical compound ClCOCC(=O)C1=CC=CC=C1 AHSPHTNFUZYFCW-UHFFFAOYSA-N 0.000 description 1
- ZFFBIQMNKOJDJE-UHFFFAOYSA-N 2-bromo-1,2-diphenylethanone Chemical compound C=1C=CC=CC=1C(Br)C(=O)C1=CC=CC=C1 ZFFBIQMNKOJDJE-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- AUYLVPGDOVEOML-UHFFFAOYSA-N [6-hydroxy-2-(4-hydroxyphenyl)-1-benzothiophen-3-yl]-[4-(piperidin-1-ylmethoxy)phenyl]methanone Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 AUYLVPGDOVEOML-UHFFFAOYSA-N 0.000 description 1
- 150000008062 acetophenones Chemical class 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 229910001513 alkali metal bromide Inorganic materials 0.000 description 1
- 229910001514 alkali metal chloride Inorganic materials 0.000 description 1
- 229910000102 alkali metal hydride Inorganic materials 0.000 description 1
- 150000008046 alkali metal hydrides Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 230000003262 anti-osteoporosis Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000010612 desalination reaction Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical compound [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 description 1
- 229910000103 lithium hydride Inorganic materials 0.000 description 1
- YWOITFUKFOYODT-UHFFFAOYSA-N methanol;sodium Chemical compound [Na].OC YWOITFUKFOYODT-UHFFFAOYSA-N 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 1
- GZUITABIAKMVPG-UHFFFAOYSA-N raloxifene Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 GZUITABIAKMVPG-UHFFFAOYSA-N 0.000 description 1
- 229960004622 raloxifene Drugs 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/22—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and doubly-bound oxygen atoms bound to the same carbon skeleton
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
Abstract
本发明涉及一种制备通式(I)的α－(3－芳硫基)－苯乙酮的方法，其中取代基R1和R2独立地代表C1－C6烷基、其中取代基R3为C1－C6烷基的SiR3 3或任选取代的苯基或苄基。本发明的特征在于使其中取代基X代表Cl或Br的通式(II)的苯乙酮与其中M代表碱金属的通式(III)的硫醇盐在甲醇中反应。
Description
本发明涉及一种制备通式I的α-(3-芳硫基)-苯乙酮的改进方法：
其中取代基R1和R2各自独立地为C1-C6烷基、其中取代基R3为C1-C6烷基的SiR3 3或任选取代的苯基或苄基。
式I化合物在药物活性物质的合成中是有价值的中间体；1-(4-甲氧基苯基)-2-[(3-甲氧基苯基)硫基]乙酮(R1，R2＝甲基)是制备抗骨质疏松活性成分雷洛昔芬(Raloxifen)的结构单元。
制备通式I的苯乙酮的各种方法是已知的。起始化合物在大多数情况下为通式II的苯乙酮：
其中取代基X为氯或溴并且取代基R1的定义如上。使这些化合物与硫醇：
-在由乙酸乙酯和氢氧化钾溶液组成的两相体系中反应(WO 02/42261)
-在乙醇/水/乙酸乙酯混合物与氢氧化钾中反应(Tetrahedron Letters(四面体快报)40(1999)2909)
-在乙醇与氢氧化钾溶液中反应(US 4,133,814)
-在乙醇/水混合物与氢氧化钾溶液中反应(US 4,418,068)。
通过这些方法得到的特别受欢迎的1-(4-甲氧基苯基)-2-[(3-甲氧基苯基)硫基]乙酮的最高产率为86％。
本发明的目的是提供一种可使有价值产物的产率更高的方法。
我们已经发现该目的通过使通式II的苯乙酮：
其中取代基X为Cl或Br并且取代基R1为C1-C6烷基、其中取代基R3为C1-C6烷基的SiR3 3或任选取代的苯基或苄基，
与通式III的硫醇盐在甲醇中反应而实现：
其中M为碱金属。
本发明方法用来制备通式I的化合物，优选制备1-(4-甲氧基苯基)-2-[(3-甲氧基苯基)硫基]乙酮。
一种起始化合物为通式II的氯代苯乙酮或溴代苯乙酮，其中取代基R1为C1-C6烷基如甲基、乙基、异丙基、正丁基或异丁基，苯基或苄基，其中所述苯基或苄基可以带有在反应条件下呈惰性的取代基如卤素或烷氧基，或取代基R1为三(C1-C6)烷基甲硅烷基，优选三甲基甲硅烷基。R1优选为短链烷基，尤其是甲基。这些化合物可以本身已知的方式，例如通过使苯乙酮类化合物与硫酰氯(US 5,710,341)或与溴(Chem.Ber.1953，86，1556)反应而得到。
使通式II的苯乙酮与通式III的硫醇盐反应，其中取代基R2为C1-C6烷基如甲基、乙基、异丙基、正丁基或异丁基，苯基或苄基，其中所述苯基或苄基可以带有在反应条件下呈惰性的取代基如卤素或烷氧基，或取代基R2为三(C1-C6)烷基甲硅烷基，优选三甲基甲硅烷基。R2优选为短链烷基，尤其是甲基。
硫醇盐阳离子M为碱金属如锂、钠或钾。硫醇盐可以通过将对应的硫醇脱质子化而制备。为此，使硫醇与碱强度足以使硫醇脱质子化的碱反应。这可以在分开的反应中进行并分离硫醇盐，但优选原位制备硫醇盐并然后转化为通式I的苯乙酮。用于原位制备硫醇盐的碱优选为碱金属氢氧化物如氢氧化钾和氢氧化钠，碱金属氢化物如氢化锂和氢化钠，碱金属氨化物如氨基锂、氨基钠和氨基钾以及碱金属醇盐如甲醇钠和甲醇钾。特别优选甲醇钠。
通式II的氯代苯乙酮或溴代苯乙酮与通式III的硫醇盐的反应在甲醇中进行。甲醇也可以含有少量其它极性溶剂如水，但优选不超过5重量％。
起始化合物的摩尔比通常为每摩尔通式II的氯代苯乙酮或溴代苯乙酮0.8-2.0mol、优选0.9-1.05mol通式III的硫醇盐。
反应可以例如在搅拌釜中进行。优选首先将通式II的氯代苯乙酮或溴代苯乙酮供入甲醇中。
甲醇的量基于100g所用通式II的苯乙酮一般为100-1000g，优选150-200g。为此，优选将通式III的硫醇盐计量加入甲醇中，并且对于100g所用的苯硫酚使用100-1000g，优选150-200g甲醇。
反应可以在大气压力和优选0-50℃的温度下进行。反应的结束例如可以通过气相色谱来检测。
通式I的广受欢迎的有价值产物仅微溶于甲醇，并因此在反应中作为固体而获得。可以将它们通过过滤以简单的方式分离。通过水洗的方法可以容易地除去在反应中形成并沉淀的碱金属氯化物或溴化物。
本发明方法可以以高产率制备通式I的化合物，另外，从工艺技术角度来看，可以以简单的方式实施该方法。
实施例1
制备1-(4-甲氧基苯基)-2-[(3-甲氧基苯基)硫基]乙酮
首先在2升搅拌装置中将216g(1.54mol)3-甲氧基苯硫酚供入253g(320ml)甲醇中。在最高为35℃的温度下，滴加275g(1.51mol)30％的甲醇钠甲醇溶液。然后将另外127g(160ml)甲醇加入混合物中。
在最高为35℃的温度下在5升搅拌烧瓶中，将上述3-甲氧基苯硫酚盐滴加入在494g(624ml)甲醇中的285g(1.54mol)氯代甲氧基苯乙酮中。将混合物在室温下搅拌10分钟，然后在0℃下搅拌1小时。吸滤出晶体，用1.5升水洗涤使其脱盐，然后用928ml甲醇洗涤。将无色产物在30℃下减压干燥。
产率：424g(1.47mol)：97.4％且纯度为99.3％(GC面积％)
Claims (4)
1.一种制备通式I的α-(3-芳硫基)-苯乙酮的方法，
其中取代基R1和R2各自独立地为C1-C6烷基、其中取代基R3为C1-C6烷基的SiR3 3或任选取代的苯基或苄基，
该方法包括使通式II的苯乙酮：
其中取代基X为Cl或Br，
与通式III的硫醇盐在甲醇中反应：
其中M为碱金属。
2.如权利要求1所要求的方法，其中制备1-(4-甲氧基苯基)-2-[(3-甲氧基苯基)硫基]乙酮。
3.如权利要求1或2所要求的方法，其中M为钠。
4.如权利要求1-3中任一项所要求的方法，其中通式III的硫醇盐通过使合适的硫醇与甲醇钠反应而制备。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10349249A DE10349249A1 (de) | 2003-10-20 | 2003-10-20 | Verfahren zur Herstellung von alpha-(3-Arylthio)-acetophenonen |
| DE10349249.6 | 2003-10-20 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1871210A true CN1871210A (zh) | 2006-11-29 |
Family
ID=34428523
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2004800309522A Pending CN1871210A (zh) | 2003-10-20 | 2004-10-14 | 制备α－(3－芳硫基)－苯乙酮的方法 |
Country Status (10)
| Country | Link |
|---|---|
| US (1) | US20070060776A1 (zh) |
| EP (1) | EP1678127B1 (zh) |
| JP (1) | JP2007509092A (zh) |
| KR (1) | KR20060100430A (zh) |
| CN (1) | CN1871210A (zh) |
| AT (1) | ATE368028T1 (zh) |
| BR (1) | BRPI0415544A (zh) |
| CA (1) | CA2541844A1 (zh) |
| DE (2) | DE10349249A1 (zh) |
| WO (1) | WO2005042477A1 (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101812002A (zh) * | 2010-04-16 | 2010-08-25 | 山东新华制药股份有限公司 | 4-甲氧基-α-[(3-甲氧基苯基)硫代]苯乙酮的合成工艺 |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4133814A (en) * | 1975-10-28 | 1979-01-09 | Eli Lilly And Company | 2-Phenyl-3-aroylbenzothiophenes useful as antifertility agents |
| US4418068A (en) * | 1981-04-03 | 1983-11-29 | Eli Lilly And Company | Antiestrogenic and antiandrugenic benzothiophenes |
| DE19511861A1 (de) * | 1995-03-31 | 1996-10-02 | Basf Ag | Verfahren zur Herstellung von a-Chloralkylarylketonen |
-
2003
- 2003-10-20 DE DE10349249A patent/DE10349249A1/de not_active Withdrawn
-
2004
- 2004-10-14 EP EP04790384A patent/EP1678127B1/de not_active Expired - Lifetime
- 2004-10-14 WO PCT/EP2004/011521 patent/WO2005042477A1/de active IP Right Grant
- 2004-10-14 BR BRPI0415544-0A patent/BRPI0415544A/pt not_active IP Right Cessation
- 2004-10-14 CN CNA2004800309522A patent/CN1871210A/zh active Pending
- 2004-10-14 JP JP2006536001A patent/JP2007509092A/ja not_active Withdrawn
- 2004-10-14 US US10/575,539 patent/US20070060776A1/en not_active Abandoned
- 2004-10-14 KR KR1020067009758A patent/KR20060100430A/ko not_active Application Discontinuation
- 2004-10-14 CA CA002541844A patent/CA2541844A1/en not_active Abandoned
- 2004-10-14 AT AT04790384T patent/ATE368028T1/de not_active IP Right Cessation
- 2004-10-14 DE DE502004004457T patent/DE502004004457D1/de not_active Expired - Fee Related
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101812002A (zh) * | 2010-04-16 | 2010-08-25 | 山东新华制药股份有限公司 | 4-甲氧基-α-[(3-甲氧基苯基)硫代]苯乙酮的合成工艺 |
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| Publication number | Publication date |
|---|---|
| WO2005042477A1 (de) | 2005-05-12 |
| DE10349249A1 (de) | 2005-05-12 |
| KR20060100430A (ko) | 2006-09-20 |
| EP1678127A1 (de) | 2006-07-12 |
| BRPI0415544A (pt) | 2006-12-26 |
| CA2541844A1 (en) | 2005-05-12 |
| EP1678127B1 (de) | 2007-07-25 |
| ATE368028T1 (de) | 2007-08-15 |
| US20070060776A1 (en) | 2007-03-15 |
| JP2007509092A (ja) | 2007-04-12 |
| DE502004004457D1 (de) | 2007-09-06 |
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