CN1772750A - (R)-N-(3-fluoro-4-morpholine phenyl)-oxazolone-5-methyl alcohol preparation process - Google Patents

Abstract

The present invention discloses the preparation process of Linezolid, and the preparation process includes the following steps: condensation of morpholine and 3, 4-difluoro nitrobenzene; reduction into 3-fluoro-4-morpholinyl aniline under the catalysis of Fe, and acylation with phosgene into 3-fluoro-4-morpholinylphenyl isocyanate; cyclization with (R)-butyl glycidate to produce (R)-N-(3-fluoro-4-morpholinylphenyl)-oxazolone-5-methyl alcohol; and further conventional synthesis steps. The present invention has simple technological process, mild reaction condition, cheap catalyst and low production cost, and is favorable to industrial production.

Description

(R)-N-(3-fluoro-4-morpholine phenyl)-oxazolone-5-methyl alcohol preparation process

(1) Technical field

The present invention relates to a new process for the preparation of pharmaceutical intermediates, specifically an important intermediate (R)-N-(3-fluoro-4-morpholine phenyl)-oxazolone-5 involved in the synthesis of antibacterial drug Linezolid - A new process for the synthesis of methyl alcohol.

(2) Background technology

(R)-N-(3-fluoro-4-morpholine phenyl)-oxazolone-5-methyl alcohol (hereinafter referred to as oxazolone) is a new generation of antibacterial drugs (R)-N-(3 -Fluoro-4-morpholine phenyl)-2-oxo-oxazole-5-methyl-acetamide (hereinafter referred to as Linezolid or Linezolid) is an important intermediate involved in the synthesis process.

Linezolid is a newest fully synthetic chemical antibacterial drug with the chemical name (R)-N-(3-fluoro-4-morpholine phenyl)-2-oxo-oxazole-5-methyl-acetamide. It was first successfully developed by pharmacia∝Upjohn in the 1990s and approved for marketing in the United States in 2000. Linezolid is the first new type of oxazolidinone antibacterial drug used in clinical practice. It has a unique structure and mechanism of action and is not prone to drug resistance. It has the characteristics of broad-spectrum antibacterial, low toxicity and high effectiveness. Especially, it has good antibacterial effect on bacteria that other antibacterial substances cannot effectively suppress, such as methicillin-resistant aureus (MRSA), penicillin-resistant pneumococcus, and vancomycin-resistant enterococcus.

Linezolid inhibits protein synthesis in Gram-positive bacteria from an early age. As the first class of antibiotics to prevent protein synthesis in early Gram-positive bacteria. Linezolid has broad prospects for development, and Linezolid is used to treat multidrug-resistant Gram ⁺ bacteria and Mycobacterium tuberculosis infections. Good for bacteremia caused by vancomycin-resistant enterococci (VRE), pneumonia and skin infections caused by methicillin-resistant Staphylococcus aureus (MRSA), and bacteremia caused by penicillin-resistant Streptococcus pneumoniae (PRSP) It is considered to be a new type of antibacterial agent with great application value. Recently, domestic researches on the synthesis of this drug have broad antibacterial spectrum and strong antibacterial activity. Bacteria have no cross-resistance between this drug and other types of synthetic drugs, and no bacteria have been found to be resistant to this type of drug. Therefore, It can be determined that Linezolid will be promoted in recent years and will become the main drug of antibiotics. Many countries in the world are vigorously carrying out the research of oxazolidinones at present, so the new technique of researching (R)-N-(3-fluoro-morpholine phenyl)-oxazolone-5-methylalcohol is beneficial to The development of oxazolidine drugs in my country plays a role in promoting.

(R)-N-(3-fluoro-4-morpholine phenyl)-oxazolone-5-methyl alcohol compound is an important intermediate in the synthesis process of the final product Linezolid, that is, linezolid. The most typical synthetic method is the first 4 steps of the synthetic method of Linezolid disclosed in WO 95/07071 patent. The synthesis method of Linezolid is as follows:

(1) Synthesis of 3-fluoro-4-morpholine phenyl;

(2) Synthesis of 3-fluoro-4-morpholine aniline;

(3) Synthesis of N-benzyloxycarbonyl-3-fluoro-4-morpholinoaniline;

(4) Synthesis of (R)-N-[3-(3-fluoro-4-morpholine)phenyl-2-oxo-5-oxazole]methyl alcohol;

(5) Synthesis of (R)-[3-(3'-fluoro-4'-morpholine)phenyl-2-oxo-5-oxazolidinyl]methanol mesylate;

(6) Synthesis of (R)-[3-(3'-fluoro-4'-morpholine)phenyl-2-oxo-5-oxazolidinyl]methyl azide;

(7) Synthesis of Linezolid.

The reaction formula is as follows:

Morpholine 3,4-Difluoronitrobenzene 3-fluoro-4-morpholinenitrobenzene 3-fluoro-4-morpholineaniline

N-Benzoate-3-fluoro-4-morpholine aniline

(R)-N-(3-Chloro-4-morpholinephenyl)-oxazolone methyl alcohol

(R)-N-(3-chloro-4-morpholine phenyl)-oxazolone methyl azide

(R)-N-(3-Chloro-4-morpholinephenyl)-oxazolone-methylacetamide

The main drawback of this synthesis method is:

1. The original process route is long, and there are seven steps of reaction from the starting material to the final product, and each step must go through separation, purification, drying and other processes.

2. The raw materials of the original process are rare and the price is relatively high.

3. The hydrogenation reduction in the original process uses 10% palladium carbon as a catalyst, and the price is relatively high; the cyclization reaction requires a temperature of -78°C and strict reaction conditions.

(3) Contents of the invention

It is very necessary to develop a highly efficient and low-cost process route. The purpose of the present invention is to provide (R)-N-(3-fluoro-4-morpholine phenyl)-oxazolone-5- A new process for the preparation of methyl alcohol. Now the improved process route is briefly described as follows:

Using morpholine and 3,4-difluoronitrobenzene as raw materials, react and condense into 3-fluoro-4-morpholine nitrobenzene in the organic phase;

Using iron powder as a catalyst and water as a hydrogen donor in an acidic environment, using the 3-fluoro-4-morpholine nitrobenzene generated by the condensation to reduce 3-fluoro-4-morpholine aniline;

Using phosgene as an acylating agent, acylate the above reduction to obtain 3-fluoro-4-morpholine anilide to obtain 3-fluoro-4-morpholine benzene isocyanate;

In the absence of water, the 3-fluoro-4-morpholine benzene isocyanate formed by the acylation of phosgene reacts with (R)-glycidyl butyrate in the organic phase to generate (R)-N-(3- Fluoro-4-morpholinephenyl)-2oxo-oxazolone-5-methylbutyrate;

The (R)-N-(3-fluoro-4-morpholine phenyl)-2 oxo-oxazolone-5-methylbutyrate generated by the above-mentioned esterification-cyclization was mixed with sodium methylate at room temperature The reaction produces (R)-N-(3-fluoro-4-morpholinephenyl)-oxazolone-5-methyl alcohol.

Since (R)-N-(3-fluoro-morpholine phenyl)-oxazolone-5-methylalcohol has no meaning in itself, its main function is as an intermediate for the synthesis of Linezolid. The above description can also be used as a pre-process for synthesizing Linezolid, and the subsequent process steps are consistent with known techniques.

The invention has the advantages that the improved process is simple and the reaction is mild. In terms of catalyst selection, readily available and cheap catalysts such as sodium carbonate and iron powder are widely used. Avoid expensive starting materials such as benzyl chloroformate. Therefore, the production cost is greatly reduced, and it is more conducive to the process production.

(4) Specific implementation methods

(1) Condensation: using morpholine and 3,4-difluoronitrobenzene as raw materials, using Na ₂ CO ₃ as a catalyst to generate 3-fluoro-4-morpholine nitrobenzene;

(2) Reduction—acylation: 3-fluoro-4-morpholine nitrobenzene is reduced to 3-fluoro-4-morpholine aniline under the action of catalyst iron powder and water as a hydrogen donor;

(3) 3-fluoro-4-morpholine aniline, in the case of anhydrous then through phosgene acylation to get 3-fluoro-4-morpholine benzene isocyanate:

(4) Nitrilation (condensation): 3-fluoro-4-morpholine benzene isocyanate and (R)-glycidyl butyrate are cyclized to generate (R)-N-( 3-fluoro-4-morpholine phenyl)-oxazolone-5-methylbutyrate;

(5) Cyclization, etc.: (R)-N-(3-fluoro-4-morpholine phenyl)-oxazolone-5-methylbutyrate reacts with sodium methoxide at room temperature to form (R)-N- (3-Fluoro-morpholinephenyl)-oxazolone-5-methylalcohol. The downward synthetic steps from this step reaction are the same as the original synthetic route. Eventually Linezolid is available.

Main experimental instruments: KDM thermostat electric heating mantle, electric mixer, digital display regulator, contact pressure regulator, constant temperature magnetic stirrer, electronic balance, vacuum drying oven, vacuum pump, super constant temperature water bath, rotary evaporator, UV-visible spectrophotometer meter, infrared spectrophotometer, nuclear magnetic resonance instrument, elemental analyzer, digital melting point instrument.

Experimental drugs: morpholine, 3.4-difluoronitrobenzene (Tianjin Kemiou Chemical Reagent Development Center), tetrachloromethane, 20% fuming concentrated sulfuric acid, toluene, (R)-glycidyl butyrate, lithium bromide, Anhydrous sodium carbonate, sodium bisulfite, ammonium chloride, and hydrochloric acid are all analytically pure.

Example:

(1) Synthesis of 3-fluoro-4-morpholine nitrobenzene:

20 ml of 3,4-difluoronitrobenzene (0.18 mol) was dissolved in 50 mL of C ₂ H ₅ OH and 0.5 g of anhydrous Na ₂ CO ₃ was added to the solution. Dilute 19ml (0.20mol) of morpholine with 50mL of C ₂ H ₅ OH and add to the above solution, and react for 6h under reflux (t=79°C), the reaction solution is slightly orange-yellow. After cooling, it was filtered to obtain a yellow solid. The mother liquor was distilled to obtain a small amount of orange solid. The solid phases were combined, washed twice with 120 ml of water, and vacuum-dried for 50 min (vacuum degree 0.95, t=85° C.) to obtain 33.1 g of a yellow solid. After the above solid was recrystallized with ethyl acetate, it was stored in a dark place to prevent discoloration. The yield was 81.11%. It was observed under a microscope as a yellow flaky transparent crystal, and its melting point was mp111.7- 112.5°C. (Literature value mp 111-112°C)

Yield: 91.11%

(2) Synthesis of 3-fluoro-4-morpholine aniline

Add 10g of reduced iron powder, 0.5g of NH ₄ Cl, 4ml of concentrated HCl (36%) in 200ml of water and heat to 98°C, add 5g of 3-fluoro-4-morpholine nitrobenzene, react for 1 hour, then add 3g of 3-fluoro- 4-Morpholine nitrobenzene, add 2g for the third time after 1 hour, add 1.5g of iron powder and a little ammonium chloride, control the temperature at 98°C, react for 3 hours under stirring, adjust the pH to 9, then add 1.5 Decolorize with activated carbon, stop stirring after 10 minutes, and carry out hot filtration. The Buchner funnel used for suction filtration is preheated first to prevent the product from crystallizing on the funnel. Add a little antioxidant NaHSO ₃ into the suction filtration bottle. Suction filtration gained mother liquor is cooled to room temperature, and a large amount of white crystals appear, extract and collect organic phase with 100ml ethyl acetate, then extract twice with 50ml ethyl acetate, combine organic phase, vacuum distill after drying with anhydrous sodium carbonate, obtain 6.8 g white solid, yield 78.84%, melting point 120-121 ° C, the product is sealed and dried to prevent water absorption and oxidation.

The yield of 3-fluoro-4-morpholine aniline was 78.84%.

(3) Synthesis of 3-fluoro-4-morpholine benzene isocyanate:

Introduce phosgene into 30ml of toluene solution for 30min to saturate the solution with phosgene. Add 3-fluoro-4-morpholine aniline in four batches, the amount of 3-fluoro-4-morpholine aniline added each time is 0.5g, pass through phosgene under stirring state, each batch of low temperature (0-5°C) The reaction was carried out at low temperature for 1 hour, and the reaction liquid was milky white, then the temperature was raised slowly to 70° C. for 4-5 hours, and the introduction of phosgene was stopped. Nitrogen was introduced for 30 minutes to drive away the remaining phosgene in the reactor, and the heating was stopped. Vacuum distillation gave 0.873 g of a brown liquid, with a yield of 62.11%. (Crude)

The yield of 3-fluoro-4-morpholine benzene isocyanate is 62.11%

(4) Synthesis of (R)-N-(3-fluoro-morpholine phenyl)-oxazolone-5-methyl alcohol

Add 0.1g LiBr and 0.03g tributylphosphine oxide to 5ml toluene, reflux for 1h, and then cool to 30-40°C. First add 0.25 g of 3-fluoro-4-morpholine benzene isocyanate, then add 0.144 g of R-glycidyl butyrate and 5 ml of toluene. React at 80°C for 7h and stop the reaction. Toluene was distilled off in vacuo. Dry, store, and use directly in the next reaction.

Dissolve 10 ml of sodium methoxide in 20 ml of methanol, add 0.5 g of (R)-N-(3-fluoro-morpholine phenyl)-oxazolone-5-methylbutyrate into the sodium methoxide solution, Stir at room temperature for 2 hours, stop the reaction, add 1-2 drops of water to remove the remaining sodium methoxide. A bright purple solid was obtained by filtration, and washed with ethyl acetate and n-hexane at a volume ratio of 1:1 to obtain a white solid. Dry and weigh.

The original process route has the following characteristics:

(1) The preparation of 3-fluoro-4-morpholine nitrobenzene in the original process route takes diisopropylethylamine as a catalyst and reacts under the reflux state. The amount of diisopropylethylamine is large, and the ratio of 3,4-difluoromorpholine nitrobenzene to the catalyst diisopropylethylamine is almost 1:1 (moL). The price of diisopropylethylamine is much higher than that of Na ₂ CO ₃ .

(2) In the original process route, the reduction of 3-fluoro-4-morpholine nitrobenzene in the original process route is based on palladium carbon (pd/c) as a catalyst and ammonium formate as a hydrogen donor, and its cost is relatively high.

(3) The synthesis of N-benzyloxycarbonyl-3-fluoro-4-morpholinoaniline in the original process route uses benzyl chloroformate. Benzyl chloroformate is expensive and not readily available.

(4) Synthesis of (R)-N-[3-(3-fluoro-4-morpholine)phenyl-2-oxo-5-oxazole]methyl alcohol in the original process route, reaction temperature -78°C , the harsh reaction conditions are unsuitable for industrial realization.

Features of the new process route:

(1) The preparation of 3-fluoro-4-morpholine nitrobenzene in the new process route uses Na ₂ CO ₃ as a catalyst. The price of Na ₂ CO ₃ is low, and the usage amount is small, so the cost of the reaction is greatly reduced.

(2) The reduction of 3-fluoro-4-morpholine nitrobenzene in the new process route takes Fe as a catalyst, reduced iron powder as a catalyst, and water as a hydrogen donor, which greatly reduces the cost of the reaction, but after the reaction, the iron Mud needs to be processed.

(3) In the new process route, the process route has been changed, the synthesis of N-benzyloxycarbonyl-3-fluoro-4-morpholinoaniline in the original process route has been canceled, and the synthesis of 3-fluoro-4-morpholinylaniline has been changed to phosgene acylation to obtain 3-fluoro- 4-morpholine benzene isocyanate, and then cyclized with (R)-glycidyl butyrate to generate (R)-N-(3-fluoro-4-morpholine phenyl)-oxazolone-5-methanol butyrate. The reaction condition that the cyclization in this operational route obtains oxazolone is at toluene reflux temperature (t=80 ℃), by contrast, this technique synthesis is much easier to control (the cyclization of original technique obtains oxazolone The ring is reacted at -78°C). Phosgene is dozens of times cheaper than benzyl chloroformate.

The phosgene that the acid chloride reaction participates in the reaction in this process route is a highly toxic gas. Operation must pay attention to safety. And the acid chloride reaction requires anhydrous reaction, and the product obtained also requires anhydrous when proceeding to the next step reaction, in order to prevent decomposition.

(4) The linezolid intermediate R-N-[3-(3-fluoro-4-morpholine) benzene-2-oxo-5-oxazolone] methyl butyrate obtained in the new process route, this butyrate does not have to Separation and purification, the next step reaction can be carried out directly, and the white solid (R)-N-[3-(3-fluoro-4-morpholine) benzene-2-oxo-5-oxazole can be produced by reacting with sodium methoxide at room temperature Ketone] Methanol.

(5) Compared with the original process route, the synthesis step of this process route has increased by one step, but the overall reaction conditions are mild and the reaction cost is low. In the synthesis route of the new process, the reaction is mild, and the catalyst used is low in price and low in cost.

The experimental results of each step:

(1) 3-fluoro-4-morpholine nitrobenzene:

State: yellow crystal. Melting point: 111.7-112.5°C. Reaction yield: 91.11%. Structural identification (IR, NMR, UV).

(2) 3-Fluoro-4-morpholine Nitidine:

State: white crystal. Melting point: 120-121°C. Reaction yield: 78.84%. TLC analysis: Rf=0.43 (chromatographic solution is cyclohexane/ethyl acetate solution with v/v=2/3). Structural identification (IR, NMR, UV):

(3) 3-fluoro-4-morpholine benzene isocyanate:

Reaction yield: 62.11%. TLC analysis: Rf=0.92 (chromatographic solution is cyclohexane/ethyl acetate solution of v/v=2/1.5).

(4) (R)-N-(3-fluoro-morpholine phenyl)-oxazolone-5-methyl alcohol:

State: white crystal or light yellow crystal. Melting point: 110°C. Reaction yield: 53.1%.

Claims (5)

1. (R)-N-(3-fluoro-4-morpholine phenyl)-oxazolone-5-methyl alcohol preparation process is characterized in that it is completed by the following steps: Using morpholine and 3,4-difluoronitrobenzene as raw materials, react and condense into 3-fluoro-4-morpholine nitrobenzene in the organic phase; Using iron powder as a catalyst and water as a hydrogen donor in an acidic environment, using the 3-fluoro-4-morpholine nitrobenzene generated by the condensation to reduce 3-fluoro-4-morpholine aniline; Using phosgene as an acylating agent, acylate the above reduction to obtain 3-fluoro-4-morpholine anilide to obtain 3-fluoro-4-morpholine benzene isocyanate; In the absence of water, the 3-fluoro-4-morpholine benzene isocyanate formed by the acylation of phosgene reacts with (R)-glycidyl butyrate in the organic phase to generate (R)-N-(3- Fluoro-4-morpholinephenyl)-2oxo-oxazolone-5-methylbutyrate; The (R)-N-(3-fluoro-4-morpholine phenyl)-2 oxo-oxazolone-5-methylbutyrate generated by the above-mentioned esterification-cyclization was mixed with sodium methylate at room temperature The reaction produces (R)-N-(3-fluoro-4-morpholinephenyl)-oxazolone-5-methyl alcohol. 2. (R)-N-(3-fluoro-4-morpholine phenyl)-oxazolone-5-methyl alcohol preparation process according to claim 1, is characterized in that described morpholine and 3, The catalyst used in the condensation reaction of 4-difluoronitrobenzene is Na ₂ CO ₃ . 3. (R)-N-(3-fluoro-4-morpholine phenyl)-oxazolone-5-methyl alcohol preparation process according to claim 1 is characterized in that described acidic environment is concentrated Hydrochloric acid and NH ₄ Cl formation. 4. (R)-N-(3-fluoro-4-morpholine phenyl)-oxazolone-5-methyl alcohol preparation process according to claim 1 is characterized in that 3-fluoro-4-morpholine During the reaction process of forming 3-fluoro-4-morpholine aniline from morpholine nitrobenzene, 3-fluoro-4-morpholine nitrobenzene is added in batches. 5. (R)-N-(3-fluoro-4-morpholine phenyl)-oxazolone-5-methyl alcohol preparation process according to claim 1 is characterized in that during the phosgene acylation reaction process Phosgene is fed in batches.