CN113493386B - Novel high-selectivity asymmetric synthesis process of 2-fluorocyclopropylamine - Google Patents

Abstract

The invention relates to a novel high-selectivity asymmetric synthesis process of 2-fluorocyclopropylamine, which is characterized in that 1-fluoro-1-benzene (sulfinyl) methane and chiral epichlorohydrin are used for constructing chiral cyclopropane under an alkaline condition, and the novel synthesis route not only achieves specific cis-trans selectivity, but also has high specific stereoselectivity. The method has the advantages of high efficiency of synthetic route and mild reaction condition, is suitable for large-scale industrial production in green environment, and greatly reduces the production cost of 2-fluorocyclopropylamine.

Description

Novel high-selectivity asymmetric synthesis process of 2-fluorocyclopropylamine

Technical Field

The invention relates to a novel high-selectivity asymmetric synthesis method of starting material 2-fluorocyclopropylamine of chemical drug sitafloxacin.

Background

Sitafloxacin was developed by the first Sanco corporation (Daiichi Sankyo) and marketed under the trade name of Japanese Pharmaceutical and Medical Device Association (PMDA) at 25/1/2008 and national drug administration (NMPA) at 2/2019 after approval by the first Sanco corporationSitafloxacin is a fluoroquinolone antibiotic. The composition is suitable for treating various infections such as respiratory system infection, urinary system infection, gynecological infection, otorhinological infection, and dental infection.

Sitafloxacin is taken as a novel broad-spectrum quinolone antibacterial agent, and imitation pharmacy is marketed in China, korea and other countries in recent years, so that the market prospect is quite good. With the marketing of sitafloxacin simulated pharmacy, the cost control of raw material medicines becomes a key factor of market competition more and more. One side chain contained in the sitafloxacin structure is chiral 2-fluorocyclopropylamine, and the synthesis difficulty and the cost of the fragment are high, so that the price of the sitafloxacin bulk drug is high, and the market popularization is not facilitated. Therefore, development of novel and efficient low-cost synthetic techniques for 2-fluorocyclopropylamine is imperative.

The current methods for synthesizing 2-fluorocyclopropane carboxylic acid are as follows.

Method one the preparation of carbenes by using polyhalogenated alkanes, a one pot process gives cyclopropane intermediates. Bayer pharmaceuticals use butadiene as a starting material in a published 1990 process to oxidize excess alkenyl groups on the resulting cyclopropane intermediate to form 2-fluorocyclopropanecarboxylic acid (j. Of fluoro chem.,1990, 49, 127).

When cheap dichloro-fluoromethane is used as a starting material, the method is low in activity and difficult to generate carbene, so that the cyclopropanation reaction yield is low (31 percent); if expensive dibromomonofluoromethane is used as the starting material, however, it is extremely costly due to its low atomic utilization. Particularly, the product obtained by the method is very poor in cis-trans ratio and can be separated through very complicated steps, so that the cost is increased, and the atom economy is sacrificed.

The second method was developed in 1995 by the first three co-pharmaceutical company, using freon to react with thiophenol, and the resulting phenyl sulfide reacted with t-butyl acrylate to give the corresponding cyclopropane intermediate (JPH 0717945).

The advantage of this process is that very good cis-trans selectivity is obtained, but the corresponding isomer is obtained, requiring further resolution to lose half of the product. In addition, high-concentration potassium hydroxide solution and sodium hydroxide solution are needed in the production process, heating is needed, the requirement on equipment is high, and a large amount of process wastewater is generated, so that the environment protection is not facilitated. The reaction conditions are severe, which results in a large number of side reactions, and the separation of the products must be rectified. And because the boiling point of the product is very high, the rectification is difficult to realize in a factory.

Method three was the Michael addition of t-butyl acrylate developed by the first three co-pharmaceutical company in 1996 (Tetrahedron Lett.1996, 47, 8507). The reaction was carried out at ultra low temperature using NaHMDS as base in a yield of 51%. And obtaining intermediate sulfoxide, and then reacting with fluorine gas to obtain a 2-fluoro intermediate.

The advantage of this process is also that very good cis-trans selectivity is obtained, but the corresponding isomer is obtained, requiring further resolution with half the loss of product. Meanwhile, the method uses ultralow temperature reaction in the first step, and has high equipment requirement and high cost; the second step uses fluorine gas, which has great problems in terms of operability and safety due to strong corrosiveness and oxidability, and is not suitable for industrial production.

Method IV is cycloaddition reaction of ethyl diazoacetate and fluoroolefin. Addition reactions of carbenes with carbon-carbon double bonds are one of the classical methods for synthesizing cyclopropanes. The first co-owned patent WO20100005003 in 2009 describes the use of an asymmetric copper catalyst to catalyze the cycloaddition of 1, 1-fluorochloroethylene to ethyl diazoacetate.

The method has the advantages that the reaction steps are shorter, the enantioselective asymmetric synthesis with certain selectivity is realized by using the chiral catalyst, but the cis-trans selectivity is still poor, the 1, 1-fluorochloroolefin used by the method is gas, and the method is easy to escape due to the release of nitrogen in the reaction process, so that the dosage of the method is greatly excessive, and the process is unstable. Also this reaction requires a closed reaction, resulting in a high safety risk in production.

The fifth method is rhodium catalyzed method developed in 2014 by the japanese apricot forest pharmaceutical. Based on the second method, 1-fluoro-1-benzenesulfonyl ethylene is used to replace 1, 1-fluorochloro olefin for carbene reaction, the ratio of trans/cis in the obtained intermediate reaches 86/14, the cis-trans selectivity is greatly enhanced, and the adopted chiral catalyst can reach more than 90% of enantioselectivity.

The method avoids using 1, 1-chlorofluoroalkene and 1-fluoro-1-benzenesulfonyl ethylene, and the method avoids the problem of gas escape in the fourth method, but the preparation of the 1-fluoro-1-benzenesulfonyl ethylene is difficult and has high cost (the synthetic route is as follows):

to sum up, no method reported in the literature so far can specifically solve the selectivity of cis-trans isomers and can specifically and asymmetrically synthesize chiral center-specific (1R, 2S) -2-fluorocyclopropylamine in the synthesis of starting materials 2-fluorocyclopropylamine and precursors thereof of sitafloxacin, thereby seriously impeding the application of sitafloxacin in disease treatment.

Disclosure of Invention

Aiming at the defects existing in the prior art, the invention aims to provide a simple, efficient and low-cost method for preparing (1R, 2S) -2-fluorocyclopropylamine (structural formula I) suitable for industrial production

The synthesis method not only achieves specific cis-trans selectivity, but also obtains the (1R, 2S) -2-fluorocyclopropylamine monomer with optical purity stereospecifically. The commercial product toluene sulfonate has the following structure (CAS: 143062-84-4)

The synthetic route of the novel high-selectivity asymmetric synthesis method of the 2-fluorocyclopropylamine is shown as the following formula:

as shown in the formula, firstly, starting from a compound SMA (1-fluoro-1 benzenesulfonyl methane or 1-fluoro-1 benzenesulfonyl methane), under the action of alkali, the compound SMA reacts with chiral epichlorohydrin in a solvent to generate absolute configuration chiral substituted cyclopropane compound INA with specific configuration (100% trans), and the compound INA reacts with an oxidizing reagent to generate a compound INB with absolute chiral configuration. The method comprises the steps that a degradation reaction is carried out on a compound INB under the condition of a conventional Curtius reaction to obtain an absolute configuration chiral amine compound INC, finally, benzene sulfonyl of the compound INC is removed under the condition that magnesium metal is in an alcohol solvent or a trace amount of mercury chloride is catalyzed to obtain a specific configuration chiral compound IND, and the IND is subjected to protective group removal to obtain a compound I which forms salt with toluene sulfonic acid to obtain a commercial compound CAS:143062-84-4. In addition, the compound INB can also remove benzenesulfonyl to a commercial chiral compound SMB with a specific configuration under the condition that magnesium metal is in an alcohol solvent or is catalyzed by a trace amount of mercury chloride.

The base used in the first step of the reaction to obtain compound INA from compound SMA is selected from sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium amide, lithium salt, sodium salt or potassium salt of LDA and HMDS, and the solvent is selected from THF, diethyl ether and methyltetrahydrofuran.

The oxidizing agent used in the second reaction step from compound INA to compound INB is selected from Jones' reagent, potassium permanganate, sodium hypochlorite and TEMPO catalyzed sodium hypochlorite.

In the third reaction step, R protecting agent in compound INC is selected from Boc and Cbz obtained by re-shooting compound INB through Curtius.

The fourth step of the reaction is to remove benzenesulfonyl group from compound INC to obtain compound IND, wherein the reagent contains magnesium metal, and the reaction is carried out in methanol, ethanol and isopropanol, preferably ethanol, and 1% -10% equivalent of mercuric chloride can be added in the reaction process to accelerate the reaction.

The initial material SMA can be thiophenol and paraformaldehyde under the action of concentrated hydrochloric acid to obtain a compound chloromethyl phenyl sulfide RA; reacting chloromethyl phenyl sulfide RA with CsF to obtain fluoromethyl phenyl sulfide RB; the compound fluoromethylphenyl sulfide RB undergoes oxidation reaction in reagents such as oxidant hydrogen peroxide, peracetic acid, m-chloroperoxybenzoic acid or potassium permanganate to obtain 1-fluoro-1-benzenesulfonyl methane or 1-fluoro-1-benzenesulfonyl methane SMA. The specific synthetic route is as follows:

in conclusion, compared with the prior art, the method disclosed by the invention has the advantages of simpler operation, less material consumption and environmental friendliness. The process of the invention has the advantages of cost, suitability for industrial mass production and capability of ensuring the cost competitiveness and continuous supply of sitafloxacin raw material medicines.

List of abbreviations

LDA diisopropylamine lithium

TEMPO 2, 6-tetramethylpiperidine nitroxide

HMDS hexamethyldisilazane

Detailed Description

Example 1: synthesis of 1-fluoro-1-phenylsulfinylmethane (Compound 4).

Step one: compound (2) was synthesized.

Paraformaldehyde (45 g,1.5 mol) was dissolved in toluene (300 mL), and concentrated hydrochloric acid (500 mL) was slowly added at room temperature. The reaction solution was heated to 40℃and stirred for 1 hour, followed by the addition of thiophenol (110 g,1 mol). The reaction was stirred at 60 ℃ for 2 hours, then cooled to room temperature and stirred overnight. The organic phase was separated and washed twice with water (250 mL). The aqueous phases were combined and extracted once with toluene (500 mL). The organic phases were combined and washed twice with saturated brine (400 mL). The organic phase was dried over anhydrous sodium sulfate. After filtration, concentration and rectification, compound 2 (128.5 g, yield 81%) was obtained.

Step two: compound (3) was synthesized.

Compound 2 (15.9 g,0.1 mol) and CsF (31.9 g,0.21 mol) were dissolved in PEG-200/acetonitrile (1:2, 90 mL). The reaction was stirred at 80℃for 3 hours under the protection of liquid nitrogen. The reaction solution was cooled to room temperature, and then water (250 mL) was added. The solution was extracted twice with chloroform (250 mL). The organic phase was separated and dried over anhydrous sodium sulfate. The organic solvent was distilled off under reduced pressure by filtration to give compound 3 (12.8 g, yield 90%).

Step three: compound (4) was synthesized.

Compound 3 (14.2 g,0.1 mol) was dissolved in dichloromethane (200 mL). The solution was cooled to 0deg.C and mCPBA (75%, 24.1g,0.105 mol) was added. The reaction solution was stirred at 0℃for 1 hour, and then 1M aqueous sodium hydroxide solution (150 mL) was added. The organic phase was separated and the aqueous phase extracted three times with dichloromethane (200 mL). The organic phases were combined and dried over anhydrous magnesium sulfate. The organic solvent is filtered and concentrated under pressure to obtain crude products. Purification of the crude product on a silica gel column (petroleum ether: ethyl acetate=6:4) afforded compound 4 (9.48 g, 60% yield).

Example 2: synthesis of 1-fluoro-1-benzenesulfonylmethane (Compound 5).

Compound 3 (14.2 g,0.1 mol) was dissolved in dichloromethane (200 mL). The solution was cooled to 0deg.C and mCPBA (75%, 57.6g,0.25 mol) was added. The reaction mixture was warmed to room temperature and stirred for 5 hours, and then 1M aqueous sodium hydroxide solution (300 mL) was added. The organic phase was separated and the aqueous phase extracted three times with dichloromethane (200 mL). The organic phases were combined and dried over anhydrous magnesium sulfate. The organic solvent is filtered and concentrated under pressure to obtain crude products. Purification of the crude product on a silica gel column (petroleum ether: ethyl acetate=4:1) afforded compound 5 (13.9 g, 80% yield).

Example 3: synthesis of (1R, 2S) -2-fluorocyclopropylamine p-toluenesulfonate salt (Compound 11).

Step one: compound (7) was synthesized.

Compound 4 (7.9 g,0.05 mol) and compound 6 (4.6 g,0.05 mol) were dissolved in THF/HMPA (13:1, 140 mL). The solution was cooled to-70℃and LiHMI) S (1M, 55mL,0.055 mol) was added. The reaction solution was stirred at-70℃for 30 minutes, and then a saturated ammonium chloride solution (50 mL) was added. The reaction mixture was warmed to room temperature, and ethyl acetate (150 mL) was added. The organic phase was separated and the aqueous phase was extracted twice with ethyl acetate (150 mL). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered and the organic solvent was concentrated under pressure to give the crude product. Purification of the crude product on a silica gel column (petroleum ether: ethyl acetate=6:4) afforded compound 7 (7.49 g, yield 70%).

Step two: compound (8) was synthesized.

Compound 7 (10.7 g,0.05 mol) was added to a mixed solution of toluene (150 mL) and water (200 mL), followed by potassium permanganate (23.7 g,0.15 mol) and tetra-n-butylammonium bromide (2.58 g,0.8 mmol). The reaction was stirred at room temperature overnight. After completion of the reaction, a 2N hydrochloric acid solution (150 mL) and ethyl acetate (300 mL) were added to the reaction mixture. The organic phase was separated and the aqueous phase was extracted twice with ethyl acetate (300 mL). The organic phases were combined and dried over anhydrous sodium sulfate. After filtration and concentration of the organic solvent under reduced pressure, compound 8 (10.37 g, yield 85%) was obtained.

Step three: compound (9) was synthesized.

Compound 8 (14.64 g,0.06 mol) was dissolved in t-butanol (290 mL) and DPPA (21.45 g,0.078 mol) and triethylamine (7.27 g,0.072 mol) were added. The reaction solution was heated to reflux for 4 hours. The reaction solution was concentrated under reduced pressure to remove the organic solvent, and the residue was dissolved in ethyl acetate (300 mL) and washed with saturated ammonium chloride (150 mL), saturated sodium bicarbonate (150 mL) and saturated brine (150 mL), respectively. The organic solvent was dried over anhydrous magnesium sulfate. Filtering, and concentrating under reduced pressure to obtain crude product. Purification of the crude product on a silica gel column (petroleum ether: ethyl acetate=4:1) afforded compound 9 (12.7 g, 67% yield).

Step three: compound (10) was synthesized.

Compound 9 (15.75 g,0.05 mol) was dissolved in methanol (150 mL) and magnesium powder (3.6 g,0.15 mol) was added at 4deg.C. The reaction solution was stirred at room temperature for 3 hours, and then poured into 5% aqueous hydrochloric acid (200. 200 mL). The mixture was extracted twice with ethyl acetate (300 mL). The organic phases were combined, washed with saturated sodium bicarbonate solution (300 mL) and saturated brine (300 mL), and then dried over anhydrous sodium sulfate. Filtering, and concentrating under reduced pressure to obtain crude product. Purification of the crude product on a silica gel column (petroleum ether: ethyl acetate=10:1) afforded compound 10 (6.91 g, 79% yield).

Step four: compound (11) was synthesized.

Compound 10 (7 g,0.04 mol) was dissolved in acetonitrile (100 mL) and p-toluenesulfonic acid (20.64 g,0.12 mol) was added. The reaction solution was stirred at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure. The residue was slurried with n-hexane/ethanol to give compound 11 (7.7 g, yield 78%).

Example 4: synthesis of (1R, 2S) -2-fluoro-2- (benzenesulfonyl) cyclopropylamine-1-carboxylic acid (Compound 8).

Step one: compound (12) was synthesized.

Compound 5 (8.7 g,0.05 mol) and sodium ethoxide (20%, 100 mL) were dissolved in ethanol (100 mL). The solution was stirred at room temperature for 30 minutes, then Compound 6 (4.6 g,0.05 mol) was added. The reaction was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the residue was poured into water (200 mL). The aqueous solution was extracted twice with ethyl acetate (400 mL). The organic phases were combined and dried over anhydrous sodium sulfate. Filtering, and evaporating the solvent under reduced pressure to obtain a crude product. Purification of the crude product on a silica gel column (petroleum ether: ethyl acetate=4:1) afforded compound 12 (9.5 g, yield 83%).

Step two: compound (8) was synthesized.

Compound 12 (11.5 g,0.05 mol) was added to a mixed solution of toluene (150 mL) and water (200 mL), followed by potassium permanganate (23.7 g,0.15 mol) and tetra-n-butylammonium bromide (2.58 g,0.8 mmol). The reaction was stirred at room temperature overnight. After completion of the reaction, a 2N hydrochloric acid solution (150 mL) and ethyl acetate (300 mL) were added to the reaction mixture. The organic phase was separated and the aqueous phase was extracted twice with ethyl acetate (300 mL). The organic phases were combined and dried over anhydrous sodium sulfate. After filtration and concentration of the organic solvent under reduced pressure, compound 8 (10.74 g, yield 88%) was obtained.

Example 5: synthesis of (1S, 2S) -2-fluorocyclopropyl carboxylic acid (Compound 12).

Compound 8 (5 g,0.02 mol) was dissolved in methanol (50 mL) and magnesium powder (1.92 g,0.08 mol) was added at 4deg.C. The reaction solution was stirred at room temperature for 3 hours, and then poured into 5% aqueous hydrochloric acid (100 mL). The mixture was extracted twice with ethyl acetate (200 mL). The organic phases were combined, washed with saturated brine (300 mL) and dried over anhydrous sodium sulfate. Filtering, and concentrating under reduced pressure to obtain crude product. Purification of the crude product on a silica gel column (petroleum ether: ethyl acetate=1:1) afforded compound 12 (1.75 g, yield 84%).

Claims (4)

1. A method for synthesizing (1R, 2S) -2-fluorocyclopropylamine p-toluenesulfonate or compound SMB is characterized by using the following steps:

。

2. the synthetic method according to claim 1, wherein the synthetic method of (1 r,2 s) -2-fluorocyclopropylamine p-toluenesulfonate salt comprises the steps of:

(1) Starting from a compound SMA, under the action of alkali, reacting with chiral epichlorohydrin in a solvent to generate a chiral substituted cyclopropane compound INA with an absolute configuration of 100% trans;

(2) Reacting the compound INA with an oxidizing reagent to obtain a compound INB with an absolute chiral configuration;

(3) The compound INB undergoes degradation reaction under the conventional Curtius reaction condition to obtain an absolute configuration chiral amine compound INC;

(4) Removing benzenesulfonyl from the compound INC in a methanol solvent of magnesium metal to obtain chiral compound IND with a specific configuration;

(5) After removing the protecting group, adding p-toluenesulfonic acid into IND to obtain (1R, 2S) -2-fluorocyclopropylamine p-toluenesulfonate;

the synthesis method of the compound SMB comprises the following steps: removing benzenesulfonyl from compound INB in methanol solvent of magnesium metal to obtain chiral compound SMB with specific configuration.

3. The synthesis method according to claim 2, wherein: the base in the step (1) is selected from sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium amide, lithium diisopropylamide and lithium, sodium or potassium hexamethyldisilazane, and the solvent is selected from THF, diethyl ether and methyltetrahydrofuran.

4. The synthesis method according to claim 2, wherein: the oxidizing agent in step (2) is selected from jones reagent, potassium permanganate, sodium hypochlorite.