US10385000B2 - Method for synthesizing 2-fluorocyclopropane carboxylic acid - Google Patents
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- US10385000B2 US10385000B2 US16/061,880 US201716061880A US10385000B2 US 10385000 B2 US10385000 B2 US 10385000B2 US 201716061880 A US201716061880 A US 201716061880A US 10385000 B2 US10385000 B2 US 10385000B2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
- C07C315/02—Preparation of sulfones; Preparation of sulfoxides by formation of sulfone or sulfoxide groups by oxidation of sulfides, or by formation of sulfone groups by oxidation of sulfoxides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
- C07C315/04—Preparation of sulfones; Preparation of sulfoxides by reactions not involving the formation of sulfone or sulfoxide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/14—Sulfones; Sulfoxides having sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
-
- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/02—Preparation of carboxylic acids or their salts, halides or anhydrides from salts of carboxylic acids
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C61/00—Compounds having carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings
- C07C61/15—Saturated compounds containing halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/16—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C317/22—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
Definitions
- the present disclosure relates to a new method for synthesizing 2-fluorocyclopropanecarboxylic acid.
- fluorine atom Since a fluorine atom has the largest electronegativity and oxidation potential, the introduction of a fluorine atom into a drug molecule can increase the lipophilicity of the drug and improve the trans-membrane ability of the drug in a living body, without significant alteration of the volume of the drug molecular. Thus, the bioavailability of the drug would be increased.
- 9a-fluoroacetic acid cortisone prepared by introducing a fluorine atom into cortisone acetate exhibited an anti-inflammatory effect about 15 times higher than that of hydrocortisone. For the first time, the fluorine atom was proved to be efficient for increasing the biological activity of a drug.
- fluorine atoms are included by increasing drug molecules, such as atorvastatin calcium, levofloxacin, lansoprazole, efavirenz, ezetimibe and so on.
- Sitafloxacin as a new broad-spectrum quinolone-based antibacterial drug, has appeared on the market in Japan and will further come into the market in various countries such as China and South Korea in recent years. It has a very broad market prospect.
- One of the side chains of sitafloxacin is monofluorocyclopropane. The synthesis of this fragment requires a key intermediate (1S, 2S)-2-fluorocyclopropane carboxylic acid.
- the raw material of sitafloxacin is expensive, which may impair the market promotion thereof. Therefore, it is necessary to develop a novel, highly effective and cost-effective technology for the synthesis of 2-fluorocyclopropane carboxylic acid.
- carbene is prepared by using polyhalogenated alkane and a cyclopropane intermediate is obtained by a one-pot process.
- butadiene was used as a starting material and a remaining alkenyl group on the resulted cyclopropane intermediate was oxidized, thereby obtaining 2-fluorocyclopropane carboxylic acid (J. of Fluorine chem., 1990, 49, 127).
- Method II is a method developed by Daiichi Sankyo Pharmaceutical Co. Ltd. in 1995. In this method, Freon was reacted with thiophenol, and then the resulted phenyl sulfide was reacted with t-butyl acrylate to obtain a corresponding cyclopropane intermediate (JPH0717945).
- This method requires high concentration of potassium hydroxide and sodium hydroxide solutions, heating, has high requirements for the equipment, and produces a large amount of process wastewater, which is detrimental to environmental protection. Moreover, a violent reaction condition results in many side reactions, and the product must be separated through rectification. However, it is difficult to achieve the rectification in a factory, due to the high boiling point of the product.
- Method III is Michael addition of t-butyl acrylate, which was developed by Daiichi Sankyo Pharmaceutical Co. Ltd. in 1996 (Tetrahedron Lett. 1996, 47, 8507). This reaction was carried out at an ultra-low temperature and NaHMDS was used as an alkali, resulting in a yield of 51%. Then, the resulted intermediate sulfoxide was reacted with fluorine gas to produce a 2-fluoro intermediate.
- Method IV is a cycloaddition reaction of ethyl diazoacetate with fluoroolefin.
- the addition reaction of carbene with a carbon-carbon double bond is one of classical methods for the synthesis of cyclopropane.
- Patent WO20100005003 which was published by Daiichi Sankyo Pharmaceutical Co. Ltd. in 2009, cites that an asymmetric copper catalyst is used to catalyze the cycloaddition reaction of 1,1-fluorochloroethylene with ethyl diazoacetate.
- This method is a relatively classical method.
- this method uses 1, 1-fluorochloroolefin in a form of gas, which is easily escaped when releasing nitrogen during the reaction.
- 1, 1-fluorochloroolefin should be greatly excessive, and the process is unstable.
- this reaction is required to be performed under a closed condition, which leads to greater security risk in production.
- Method V is a rhodium-catalyzed method which was developed by Kyorin Pharmaceutical Co., Ltd. (Japan) in 2014. This method was based on method II, and used 1-fluoro-1-phenylsulfone ethylene, instead of 1, 1-fluorochloroalkene, to carry out the carbene reaction. In the resulted intermediate, a trans/cis ratio reached 86/14, which greatly enhanced cis/trans selectivity.
- This method uses 1-fluoro-1-benzenesulfonyl ethylene and avoids the use of 1,1-fluorochloroolefin. Although the gas escape problem in method IV above is avoided, it is difficult and costly for the preparation of the 1-fluoro-1-benzenesulfonyl ethylene (the synthesis route thereof shown as follows).
- the object of the present disclosure is to provide a new method for synthesizing 2-fluorocyclopropane carboxylic acid.
- a new method for synthesizing 2-fluorocyclopropanecarboxylic acid comprises the following steps:
- Step 3 3) performing an elimination reaction of the product obtained in Step 2) in the presence of an alkali, to obtain 1-fluoro-1-benzenesulfonyl ethylene;
- the alkali is at least one selected from alkoxide, carbonate, bicarbonate, hydroxide, and hydride of an alkali metal or alkaline earth metal.
- Step 1) the mass ratio of 1,1-dichloro-1-fluoroethane and thiophenol is (1.1-3.5):1.
- Step 2 the mass ratio of the phenyl sulfide intermediate and Oxone is 1:(7-9).
- the alkali is at least one selected from alkoxide, carbonate, bicarbonate, hydroxide and hydride of an alkali metal or alkaline earth metal and DBU.
- Step 3 the mass ratio of the product obtained in Step 2) and the alkali is (1.1-2):1.
- Step 4 the mass ratio of 1-fluoro-1-benzenesulfonylethylene and ethyl diazoacetate is (1.1-1.7):1.
- the catalyst is a rhodium-based catalyst.
- the alkali is at least one selected from alkoxide, carbonate, bicarbonate, hydroxide, hydride of an alkali metal or alkaline earth metal.
- an acid for the acidification is at least one selected from hydrochloric acid, sulfuric acid, nitric acid and perchloric acid.
- the synthetic route of the present disclosure is short, the materials used therein are bulk commodities, and the raw materials are inexpensive and readily available.
- the process can be safely scaled up by replacing commonly used mCPBA reagents with Oxone.
- FIG. 1 is a schematic diagram of a synthesis method according to the present disclosure.
- a new method for synthesizing 2-fluorocyclopropane carboxylic acid comprises the following steps:
- Step 3 3) performing an elimination reaction of the product obtained in Step 2) in the presence of an alkali, to obtain 1-fluoro-1-benzenesulfonyl ethylene;
- FIG. 1 is a schematic diagram of the synthesizing method according to the present disclosure.
- the schematic diagram is merely an example of the synthesizing method. It shall be appreciated that the method of the present disclosure is not limited to the related materials as shown in FIG. 1 .
- the alkali of Step 1) is at least one selected from alkoxide, carbonate, bicarbonate, hydroxide, and hydride of an alkali metal or alkaline earth metal. More preferably, the alkali of Step 1) is at least one selected from sodium alkoxide, potassium alkoxide, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate. Still more preferably, the alkali of Step 1) is at least one selected from sodium alkoxide, potassium alkoxide, sodium hydroxide and potassium hydroxide. Still more preferably, the alkali of Step 1) is at least one selected from sodium hydroxide and potassium hydroxide.
- the mass ratio of 1,1-dichloro-1-fluoroethane and thiophenol is (1.1-3.5):1. More preferably, in Step 1), the mass ratio of 1,1-bischloro-1-fluoroethane and thiophenol is (1.2-3.4):1. Still more preferably, in Step 1), the mass ratio of 1,1-dichloro-1-fluoroethane and thiophenol is (1.3-3.3):1.
- the mass ratio of the phenyl sulfide intermediate and Oxone is 1:(7-9). More preferably, in Step 2), the mass ratio of the phenyl sulfide intermediate and Oxone is 1:(7.2-8.8). More preferably, in Step 2), the mass ratio of the phenyl sulfide intermediate and Oxone is 1:(7.4-8.6). Still more preferably, in Step 2), the mass ratio of the phenyl sulfide intermediate and Oxone is 1:(7.6-8.4).
- the alkali of Step 3) is at least one selected from alkoxide, carbonate, bicarbonate, hydroxide, and hydride of an alkali metal or alkaline earth metal and DBU. More preferably, the alkali of Step 3) is at least one selected from sodium alkoxide, potassium alkoxide, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and DBU. More preferably, the alkali of Step 3) is at least one selected from sodium alkoxide, potassium alkoxide, sodium hydroxide, potassium hydroxide, and DBU. Still more preferably, the alkali of Step 3) is at least one selected from potassium t-butoxide, potassium hydroxide, and DBU.
- the mass ratio of the product obtained in step 2) and the alkali is (1.1-2):1. More preferably, in step 3), the mass ratio of the product obtained in Step 2) and the alkali is (1.2-1.9):1. Still more preferably, in step 3), the mass ratio of the product obtained in Step 2) and the alkali is (1.3-1.8):1.
- the solvent for the reaction of Step 3) is a polar solvent. More preferably, the solvent for the reaction of Step 3) is at least one selected from water, methanol, ethanol, propanol, isopropanol, acetone, tetrahydrofuran, dimethyl sulfoxide. Still more preferably, the solvent for the reaction of Step 3) is at least one selected from water, methanol, and tetrahydrofuran.
- the mass ratio of 1-fluoro-1-benzenesulfonylethylene and ethyl diazoacetate is (1.1-1.7):1. More preferably, in Step 4), the mass ratio of 1-fluoro-1-benzenesulfonyl ethylene and ethyl diazoacetate is (1.2-1.6):1. Still more preferably, in Step 4), the mass ratio of 1-fluoro-1-benzenesulfonylethylene and ethyl diazoacetate is (1.3-1.5):1.
- the catalyst of Step 4) is a rhodium-based catalyst. More preferably, the catalyst of Step 4) is an organic rhodium catalyst. Still more preferably, the catalyst of Step 4) is a rhodium acetate dimer. Most preferably, the catalyst of Step 4) is a rhodium triphenylacetate dimer.
- the mass ratio of the catalyst to 1-fluoro-1-phenylsulfonylethylene is 0.5-1.5%. More preferably, in Step 4), the mass ratio of the catalyst to 1-fluoro-1-phenylsulfonylethylene is 0.8-1.2%. Most preferably, in step 4), the mass ratio of the catalyst to 1-fluoro-1-benzenesulfonylethylene is 1.0%.
- the alkali of Step 5) is at least one selected from alkoxide, carbonate, bicarbonate, hydroxide, and hydride of an alkali metal or alkaline earth metal. More preferably, the alkali of Step 5) is at least one selected from sodium alkoxide, potassium alkoxide, magnesium alkoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride. Still more preferably, the alkali of Step 5) is at least one selected from magnesium ethoxide, sodium ethoxide, potassium t-butoxide, sodium hydroxide, and potassium hydroxide. Still more preferably, the alkali of Step 5) is at least one selected from magnesium ethoxide, sodium hydroxide and potassium hydroxide.
- the acid for the acidification is at least one selected from hydrochloric acid, sulfuric acid, nitric acid and perchloric acid. More preferably, in step 5), the acid for the acidification is at least one selected from hydrochloric acid and sulfuric acid. Most preferably, in step 5), the acid for the acidification is hydrochloric acid.
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Abstract
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Application Number | Priority Date | Filing Date | Title |
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CN201610686205 | 2016-08-18 | ||
CN201610686205.9A CN106316824B (en) | 2016-08-18 | 2016-08-18 | A kind of new method of synthesis 2- fluorine cyclopropane-carboxylic acids |
CN201610686205.9 | 2016-08-18 | ||
PCT/CN2017/081892 WO2018032796A1 (en) | 2016-08-18 | 2017-04-25 | Novel 2-fluorocyclopropane carboxylic acid synthesis method |
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US20180370893A1 US20180370893A1 (en) | 2018-12-27 |
US10385000B2 true US10385000B2 (en) | 2019-08-20 |
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CN106316824B (en) * | 2016-08-18 | 2018-10-19 | 广州康瑞泰药业有限公司 | A kind of new method of synthesis 2- fluorine cyclopropane-carboxylic acids |
CN109020830A (en) * | 2018-08-29 | 2018-12-18 | 广州康瑞泰药业有限公司 | A kind of methylol cyclopropyl acetonitrile derivative and its methods for making and using same |
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JPS5159839A (en) * | 1974-10-23 | 1976-05-25 | Sankyo Co | SHIKUROPUROPANKARUBONSANJUDOTAINO SEIZOHO |
GB9000130D0 (en) * | 1990-01-04 | 1990-03-07 | Ici Plc | Fungicides |
WO1995004712A1 (en) * | 1993-08-05 | 1995-02-16 | Daiichi Pharmaceutical Co., Ltd. | Selective dehalogenation method |
IS7839A (en) * | 2002-11-22 | 2004-05-23 | Merck Frosst Canada Ltd. | 4-Oxo-1- (3-substituted phenyl-1,4-dihydro-1,8-naphthyridine-3-carboxamide phosphodiesterase-4 inhibitor |
AU2008261325B2 (en) * | 2007-06-15 | 2012-12-06 | Newron Pharmaceuticals S.P.A. | Substituted 2- [2- (phenyl) ethylamino] alkaneamide derivatives and their use as sodium and/or calcium channel modulators |
CN102827042B (en) * | 2012-09-17 | 2013-11-06 | 湖北美天生物科技有限公司 | Chiral synthesis method of florfenicol |
CN106316824B (en) * | 2016-08-18 | 2018-10-19 | 广州康瑞泰药业有限公司 | A kind of new method of synthesis 2- fluorine cyclopropane-carboxylic acids |
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Non-Patent Citations (3)
Title |
---|
Diego A. Alonso, 3, 5 Bis (trifluoromethyl)phenyl Sulfones in the Synthesis of 3, 5 Disustituted Cyclopent-2-enones, ARKIVOC, 2007, p. 245. * |
Neal 0. Brace, An Economical and Convenient Syn thesis of Phenyl Vinyl Sulfone from Benzenethiol and 1,2 Dichloroethane, Journal of Organic Chemistry, 58(16), 1993. * |
Shibue et al., Stereoselective Synthesis of cis 2 Fluorocyclopropan carboxylic Acid, The Journal of Organic Chemistry, 79(15), 2014. * |
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WO2018032796A1 (en) | 2018-02-22 |
CN106316824B (en) | 2018-10-19 |
CN106316824A (en) | 2017-01-11 |
US20180370893A1 (en) | 2018-12-27 |
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