CN113801053B - Method for preparing 7-fluoro-2-oxoindoline-4-carboxylic acid - Google Patents
Method for preparing 7-fluoro-2-oxoindoline-4-carboxylic acid Download PDFInfo
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- CN113801053B CN113801053B CN202111283521.9A CN202111283521A CN113801053B CN 113801053 B CN113801053 B CN 113801053B CN 202111283521 A CN202111283521 A CN 202111283521A CN 113801053 B CN113801053 B CN 113801053B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
- C07D209/34—Oxygen atoms in position 2
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
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- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention provides a preparation method of 7-fluoro-2-oxo indoline-4-carboxylic acid, which adopts the following synthetic route:
Description
Technical Field
The invention relates to the field of organic chemical synthesis, in particular to a method for preparing 7-fluoro-2-oxo-indoline-4-carboxylic acid.
Background
Benzo [ b ] pyrrole ring derivatives are the most common family of heterocyclic motifs in natural products and include a number of prominent representatives, such as the essential alpha-amino acid tryptophan, its putrefactive products, the plant growth factor 3-indoleacetic acid (heterologous auxin), the neurotransmitter hydroxytryptamine, the pineal hormone melatonin, the rauvolfia alkaloid, reserpine and yohimbine, the ranunculus alkaloids, oval mycin, the strychnine, the ergotamine and vinca alkaloids, vincristine. However, many natural plants have very large toxic and side effects, and the toxicity of the indole family compounds can be obviously reduced and the drug effect can be improved by optimizing the structure of the indole family compounds, and medicines in a plurality of treatment fields such as antihypertensive, antiproliferative, antiviral, antitumor, analgesic, anti-inflammatory and antibacterial fields, such as octenib, sumatriptan, leuprorelin acetate, goserelin acetate and the like, are successfully developed.
CN113286586a (WO 2019243841) discloses compounds A, B and C useful for the treatment of diseases mediated by alpha 1 antitrypsin, including alpha-1-antitrypsin deficiency. Diseases mediated by alpha-1 antitrypsin include alpha-1 antitrypsin deficiency, liver dysfunction, fibrosis, cirrhosis, liver failure and hepatocellular carcinoma, pulmonary diseases, dysfunction and inflammation including asthma, COPD, emphysema and lung cancer, and skin inflammatory conditions including dermatitis and pruritus.
Wherein R is 1 Selected from H, F, CH 3 、CH 2 CH 3 、CH 2 CH 2 CH 3 、CH(CH 3 ) 2 、NH 2 、NHCH 3 、N(CH 3 ) 2 OH, cl, br and I; r is R 1 H and F are preferred. R is R 2 Selected from CH 3 、Cl、CH 2 CH 3 、CH 2 CH 2 CH 3 、CH(CH 3 ) 2 、NH 2 、NHCH 3 、N(CH 3 ) 2 OH, SH, CN, F, br and I; and R is 3 Selected from F, cl, CN, CH 3 、CH 2 CH 3 、CH 2 CH 2 CH 3 、CH(CH 3 ) 2 、NH 2 、NHCH 3 、N(CH 3 ) 2 OH, br, I and SH.
It can be seen that 7-fluoro-2-oxoindoline-4-carboxylic acid is a key intermediate for the synthesis of the above compounds A, B and C. The synthetic route reported in documents European Journal of Organic Chemistry 2006, 13, 2956-2969 is as follows:
the route takes 4-bromo-1-fluoro-2-nitrobenzene as a raw material, the indole compound is obtained by cyclization, and then the corresponding oxoindoline compound is obtained by oxidation and other processes, wherein n-butyllithium is used in the route and reacts at the temperature of minus 75 ℃, and the reaction yield is about 60% -70%; if a format reagent such as vinyl magnesium bromide is used, the yield is only 30-40%. The process has harsh conditions, uses n-butyllithium and vinyl magnesium bromide as dangerous reagents, requires a low temperature of 75 ℃ below zero, is difficult to realize large-scale industrial production, and is not suitable for green production due to a large amount of production wastewater and waste salt.
WO2011119777A2 reports a process for preparing 2-oxindole-5-carboxylic acid starting from 1H-indole-5-carboxylic acid by the following synthetic route:
bromine is used as a reagent in the above route, and has strong volatility and strong sensitization, and the large-scale production is dangerous and pollutes the environment; the metal zinc reagent is used, the activated metal zinc has stronger spontaneous combustibility, and the danger coefficient in industrial production is high; the zinc salt is difficult to treat, and the waste liquid is harmful to the environment and needs special treatment.
There is therefore a need to develop an efficient and environmentally friendly green synthesis process for the preparation of 7-fluoro-2-oxoindoline-4-carboxylic acid.
Disclosure of Invention
The present invention aims to provide a novel process for preparing 7-fluoro-2-oxoindoline-4-carboxylic acid, which solves the problems mentioned in the background art.
The invention provides a preparation method of 7-fluoro-2-oxo indoline-4-carboxylic acid, which adopts the following synthetic route:
the method specifically comprises the following steps:
step 1: adding the compound (IV) into a solvent, adding a catalyst and alkali, introducing carbon monoxide gas, and reacting to obtain a compound (V);
step 2: the compound (V) is hydrolyzed under the condition of alkali to obtain the compound (I) 7-fluoro-2-oxo indoline-4-carboxylic acid.
In a further embodiment of the invention, in step 1, the catalyst is selected from (dppf) PdCl 2 、(dppm)PdCl 2 、(dppe)PdCl 2 、(dppp)PdCl 2 、(tol-binap)PdCl 2 、(rac-binap)PdCl 2 、(dppb)PdCl 2 、(DPEphos)PdCl 2 、(phanephos)PdCl 2 、(xantphos)PdCl 2 、(norphos)PdCl 2 、PdCl 2 (PhCN)、PdCl 2 (MeCN) 2 、Pd 2 (dba) 3 、PdCl 2 (PPh 3 ) 2 、Pd(OAc) 2 、Pd(OAc) 2 Per pddf et al, preferably (dppf) PdCl 2 ；
In a further embodiment of the present invention, in step 1, the base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, N-diisopropylethylamine, pyridine, 4-dimethylpyridine, potassium acetate, sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc., preferably triethylamine;
in a further embodiment of the present invention, in step 1, the solvent is selected from the group consisting of methanol, ethanol, isopropanol, t-butanol, ethylene glycol, tetrahydrofuran, acetonitrile, and the like, preferably methanol; preferably, the pressure after introducing carbon monoxide gas into the reaction vessel is 0.1 to 2.5MPa, more preferably 0.5 to 1.0MPa, and most preferably 0.5 to 0.6MPa.
In a further embodiment of the present invention, in step 1, the ratio of the molar amount of the compound (IV) to the molar amount of the catalyst is 1: (0.001 to 0.5), preferably 1: (0.01-0.1);
in a further embodiment of the present invention, in step 1, the ratio of the molar amount of said compound (IV) to the molar amount of the base is optionally 1: (1 to 10), preferably 1: (1-4); the reaction temperature is optionally 50 to 200 ℃, preferably 110 to 130 ℃.
In a further embodiment of the present invention, in step 2, the base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc., preferably sodium hydroxide;
in a further embodiment of the present invention, in step 2, the hydrolysis is performed in one or any combination of methanol, ethanol, isopropanol, t-butanol, ethylene glycol, acetone, tetrahydrofuran, methyltetrahydrofuran or acetonitrile, preferably methanol;
in a further embodiment of the present invention, in step 2, the ratio of the molar amount of said compound (V) to the molar amount of the base is optionally 1: (1 to 10), preferably 1: (1 to 5), more preferably 1: (1.5-2.5); the reaction temperature is optionally 0 to 100℃and preferably 40 to 60 ℃.
The invention also provides a method for preparing the compound IV, which adopts the following synthetic route:
step A: adding a compound (II) 4-bromo-7-fluoroindoline-2, 3-dione into a solvent, adding hydrazine hydrate, and reacting at a proper reaction temperature to obtain a compound (III);
and (B) step (B): adding alkali into a proper reaction solvent to react the compound (III) to obtain the compound (IV).
The invention provides still further solutions: in the step A, the solvent is methanol, ethanol, isopropanol, tertiary butanol, glycol, tetrahydrofuran, methyltetrahydrofuran, acetonitrile, pyridine, N-dimethylformamide, dimethyl sulfoxide and the like, preferably glycol;
in a further embodiment of the invention, the ratio of the molar amount of compound (II) to the molar amount of hydrazine hydrate is optionally 1: (1-10), preferably 1: (1-3), further preferably 1: (1-1.5); the reaction temperature is optionally 0 to 100 ℃, preferably 30 to 80 ℃, more preferably 55 to 65 ℃.
The invention further provides the following scheme: in the step B, the reaction solvent is selected from xylene, chlorobenzene, dichlorobenzene, glycol, N-dimethylformamide, dimethyl sulfoxide and the like, preferably glycol.
The invention further provides the following scheme: the reaction time in step B is 2 to 24 hours, preferably 8 to 16 hours.
The invention further provides the following scheme: in the step B, the molar ratio of the compound (III) to the alkali is 1: (0.05-1.0), preferably 1: (0.05-0.1); the reaction temperature is optionally 100 to 200 ℃, preferably 120 to 150 ℃, more preferably 135 to 145 ℃.
The invention further provides the following scheme: in step B, the alkali is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, lithium acetate, sodium acetate, potassium acetate, cesium acetate and the like, preferably sodium acetate.
The beneficial effects of the invention are as follows:
the method uses 4-bromo-7-fluoroindoline-2, 3-dione as raw material, the raw material is easy to obtain, format reagent which is difficult to industrialize is avoided in the reaction, the safety of industrial production is improved, the yield of each step is very high, the process operation is relatively simple and convenient, and the method is suitable for industrial mass production.
The step A of the invention is particularly finished in the glycol solvent, the post-treatment is convenient, the crude product is obtained by filtration and separation, the quality of the crude product is good, and the next feeding can be directly carried out without further treatment.
In the invention, weak bases such as sodium acetate and the like are selected in the step B, dangerous reagents such as strong bases (namely sodium methoxide and sodium ethoxide) are not used, and the compound shown in the formula (IV) is obtained by strictly controlling reaction operation parameters such as the feeding ratio between reaction materials and the reaction reagents, and the reaction time is preferably 8-16 hours, so that the product purity is good, and the total reaction yield in the two steps is high and can reach 85%;
in the step 1, the CO/butyllithium reaction condition is not used, and (dppf) PdCl is selected 2 The catalyst has high catalytic activity, CO can obtain a compound shown as a high-purity intermediate formula (V) under low pressure, and the reaction yield is high;
the step 2 hydrolysis reaction has mild reaction conditions, almost quantitative yield, good reproducibility of reaction conditions, convenient industrialized amplification, and very good quality of the final 7-fluoro-2-oxo-indoline-4-carboxylic acid obtained by the method, thereby providing quality assurance for preparing indoline medicines for treating diseases mediated by alpha 1 antitrypsin, including alpha-1-antitrypsin defects.
Detailed Description
The technical solutions of the present invention will be clearly and completely described in connection with the embodiments, and it is obvious that the described embodiments are only some embodiments of the present invention, not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
In the following, all starting materials are commercially available or prepared by methods conventional in the art unless specifically indicated.
The method for preparing 7-fluoro-2-oxoindoline-4-carboxylic acid adopts the following synthetic route:
example 1
250ml of ethylene glycol and 50g (205 mmol) of the compound shown in the formula (II) and 15.4g (250 mmol) of hydrazine hydrate (80%) are added into a 500ml three-port bottle, the mixture is stirred for 30min, the internal temperature is controlled to be 55-65 ℃, the reaction is carried out for 2-6h, the central control raw material disappears, and the reaction is completed. Cooling to room temperature, filtering to obtain 60g of crude product shown in formula (III) (the subsequent reaction can be directly carried out without further treatment).
Example 2
Into a 500ml three-necked flask, 500ml of ethylene glycol was added, 60g of the crude product represented by the above-obtained (III) was added, 1.7g (20.5 mmol) of sodium acetate was added, the reaction temperature was raised to 135-145℃and the reaction was carried out for 8-16 hours, and the center control reaction was completed. Concentrating under reduced pressure to 1/3 of the original volume, cooling to 0-10 ℃, filtering, leaching with 100ml of water, and vacuum drying to obtain 40g of the compound shown in the formula (IV), wherein the purity is more than or equal to 98%.
Example 3
Into a 500ml autoclave, 300ml of methanol was added, 30g of the compound represented by the above-obtained (IV) was added, and 27ml of triethylamine (dppf) PdCl was added 2 1.55g, CO is replaced three times, and the pressure of CO in the reaction kettle is controlled to be 0.5MPa; controlling the reaction temperatureThe mixture is reacted for 10 hours at the temperature of 115-125 ℃, cooled to room temperature, concentrated in solvent, added with DMF and DCM, stirred for 30min, filtered to obtain 23g of compound shown in the formula (V), and the purity is more than or equal to 98%.
Example 4
Table 1 reaction parameters and results summary table under different conditions were changed according to the preparation method of the compound represented by formula (V) in example 3:
example 5
Into a 250ml three-necked flask, 100ml of methanol was added, 20g (95.7 mmol) of the compound represented by (V) obtained in the above example 3 or 4 was added, 7.7g of sodium hydroxide (191 mmol) was further added, and 100ml of water was stirred for 30 minutes, and the internal temperature was controlled at 40-60℃to react for 5 hours, thereby completing the reaction under a medium control. Concentrating methanol, adjusting ph=1-2 with 1M hydrochloric acid; 17.7g of the compound shown in the formula (I) is obtained by filtration, and the purity is more than or equal to 99%. Hydrogen spectrum 1 H-NMR(400MHz,DMSO-d 6 )：δ13.44-12.72(m,1H),11.01(s,1H),7.50(dd,J＝4.8,8.8Hz,1H),7.21(t,J＝9.6Hz,1H),3.75(s,2H)。
Claims (8)
1. A preparation method of 7-fluoro-2-oxo indoline-4-carboxylic acid comprises the following synthetic route:
the method specifically comprises the following steps:
step 1: adding the compound IV into a solvent, adding a catalyst and alkali, introducing carbon monoxide gas, and reacting to obtain a compound V;
step 2: hydrolyzing the compound V under the condition of alkali to obtain a compound I7-fluoro-2-oxo indoline-4-carboxylic acid;
the catalyst in the step 1 is selected from (dppf) PdCl 2 Or Pd (OAc) 2 One of/pddf or a combination thereof;
the ratio of the molar amount of compound IV to the molar amount of catalyst in step 1 is 1: (0.001-0.1);
the alkali in the step 1 is selected from one or any combination of triethylamine or N, N-diisopropylethylamine;
the ratio of the molar amount of compound IV to the molar amount of base in step 1 is 1: (1-4);
the pressure of the carbon monoxide gas introduced in the step 1 is 0.5-1.0MPa;
the reaction temperature of the step 1 is 120-130 ℃;
the solvent in the step 1 is selected from one or any combination of methanol, ethanol, isopropanol, tertiary butanol or ethylene glycol;
in the step 2, the alkali is selected from one or any combination of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide or potassium tert-butoxide;
the preparation method of the compound IV comprises the following steps:
step A: adding a compound II 4-bromo-7-fluoroindoline-2, 3-dione into a solvent, adding hydrazine hydrate, and reacting at a proper reaction temperature to obtain a compound III;
in the step A, the solvent is ethylene glycol;
in step a, the ratio of the molar amount of compound II to the molar amount of hydrazine hydrate is 1: (1-1.5), wherein the reaction temperature is 55-65 ℃;
and (B) step (B): adding alkali into a proper reaction solvent for reaction to prepare a compound IV;
in the step B, the alkali is selected from one or any combination of lithium acetate, sodium acetate, potassium acetate or cesium acetate;
in the step B, the molar ratio of the compound III to the alkali is 1: (0.05-0.1), wherein the reaction temperature is 120-150 ℃.
2. The method of manufacturing according to claim 1, characterized in that: the pressure of the carbon monoxide gas introduced in the step 1 is 0.5-0.6MPa.
3. The preparation method according to any one of claims 1 or 2, characterized in that: the hydrolysis in step 2 is performed in one or any combination of methanol, ethanol, isopropanol, tertiary butanol, ethylene glycol, acetone, tetrahydrofuran, methyltetrahydrofuran or acetonitrile.
4. The preparation method according to any one of claims 1 or 2, characterized in that: the ratio of the molar amount of compound V to the molar amount of base in step 2 is 1: (1-5); the reaction temperature is selected from 40-60 ℃.
5. The method of manufacturing according to claim 4, wherein: the ratio of the molar amount of compound V to the molar amount of base in step 2 is 1: (1.5-2.5).
6. The preparation method according to any one of claims 1 or 2, characterized in that: in the step B, the reaction solvent is selected from one or any combination of glycol, N-dimethylformamide or dimethyl sulfoxide.
7. The preparation method according to any one of claims 1 or 2, characterized in that: the reaction temperature of the step B is 135-145 ℃.
8. The preparation method according to any one of claims 1 or 2, characterized in that: the reaction time of the step B is 8-16h.
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