CN113429333A - Synthesis method of gatifloxacin intermediate - Google Patents
Synthesis method of gatifloxacin intermediate Download PDFInfo
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- CN113429333A CN113429333A CN202110773638.9A CN202110773638A CN113429333A CN 113429333 A CN113429333 A CN 113429333A CN 202110773638 A CN202110773638 A CN 202110773638A CN 113429333 A CN113429333 A CN 113429333A
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- gatifloxacin
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- 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
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
Abstract
The invention discloses a synthesis method of a gatifloxacin intermediate (1R) -5-bromo-2, 3-dihydro-1-methyl-1H-isoindole, which comprises the following steps: step 1: taking R (+) -alpha-phenylethylamine as a raw material and Lewis acid as a catalyst, and carrying out bromine bromination reaction to obtain a compound 2; step 2: placing the compound 2 in a solvent, adding hydrochloric acid, paraformaldehyde and a catalyst, and carrying out chloromethylation reaction to obtain a compound 3; and step 3: dissolving the compound 3 in a solvent, adding alkali, and heating for reaction to obtain a compound 1. The method has the advantages of simple reaction, short route, less three wastes, environmental protection, higher yield of each step, less waste of raw materials and reagents and particular suitability for industrial production.
Description
Technical Field
The invention belongs to the technical field of synthesis of a gatifloxacin intermediate, and particularly relates to a synthesis method of a gatifloxacin intermediate (1R) -5-bromo-2, 3-dihydro-1-methyl-1H-isoindole.
Background
Garafloxacin is a new quinolone drug developed by fushan corporation of japan (Toyama) together with the great positive pharmaceutical industry, and was approved for sale in japan in 2007. The injection is mainly used for treating respiratory tract and otorhinolaryngological infection, has stronger activity on multi-drug resistant streptococcus pneumoniae, and has higher activity than ciprofloxacin and trovafloxacin. Unlike previous fluoroquinolone drugs, removal of fluorine at the 6-position of the quinolone mother nucleus of gatifloxacin not only improves activity but also reduces drug toxicity. Therefore, the market of the gatifloxacin has the possibility of eliminating the serious side effect problem of the fluoroquinolone products.
The (1R) -5-bromo-2, 3-dihydro-1-methyl-1H-isoindole is a key intermediate of the gatifloxacin, and the cost of the key intermediate greatly influences the raw material cost of the gatifloxacin. Currently, the following methods are available for the synthesis of (1R) -5-bromo-2, 3-dihydro-1-methyl-1H-isoindole:
1. taking bromoacetophenone as raw material (CN106957255)
The route seems simple, but the bromoacetophenone as a raw material needs to be synthesized by oneself, and the reaction system is messy and the product is difficult to separate from the repeated results. The products in the cyclization step are mostly hydroxymethylated species and are not the target compounds of this patent.
2. Takes 3-bromo-1-phenylethylamine as raw material (Organic Letters,2018, vol.20, #9, p.2595-2598)
The raw materials of the route are not easy to prepare, the first reaction condition is harsh, and special equipment is needed. We have verified that the second reduction step requires about 12 times the molar amount of sodium borohydride and the raw material cost is too high.
3. Phthalimide is used as a raw material (WO 2014/146490; Synthetic Communications,2004, vol.34, #5, p.853-861; Tetrahedron Letters,2002, vol.43, #50, p.9163-9165)
The method has the advantages of cheap and easily obtained starting materials, expensive reagents and large dosage. In the bromination step, a lot of byproducts are generated, and the separation is difficult. The same cost is too high in the sodium borohydride reduction step and the product still needs to be resolved to obtain the desired configuration.
4. Takes p-bromophenylethylamine as raw material
The method has multiple reaction steps, harsh conditions and expensive reagents. And further, it needs to be resolved to obtain the desired configuration.
5. With polybrominated substance as raw material (US2002/173517)
The starting materials of this process are difficult to prepare and require further resolution to obtain the desired configuration.
6. 6-bromoisoindoline-1-ketone is taken as a starting material (WO 2015/150565; WO2017/68412)
The method has the advantages of difficult obtainment of initial raw materials, harsh reaction conditions in the second step, strict control of water content in the process of adopting the method and expensive reagents. And further, it needs to be resolved to obtain the desired configuration.
Disclosure of Invention
The purpose of the invention is as follows: aiming at the problems in the prior art, the invention provides a synthesis method of a gatifloxacin intermediate (1R) -5-bromo-2, 3-dihydro-1-methyl-1H-isoindole, which has the advantages of simple steps, mild conditions and relatively friendly environment.
The technical scheme is as follows: in order to achieve the purpose of the invention, the technical scheme adopted by the invention is as follows:
a synthesis method of a gatifloxacin intermediate (1R) -5-bromo-2, 3-dihydro-1-methyl-1H-isoindole comprises the following steps:
step 1: taking R (+) -alpha-phenylethylamine as a raw material and Lewis acid as a catalyst, and carrying out bromine bromination reaction to obtain a compound 2;
step 2: placing the compound 2 in a solvent, adding hydrochloric acid, paraformaldehyde and a catalyst, and carrying out chloromethylation reaction to obtain a compound 3;
and step 3: dissolving the compound 3 in a solvent, adding alkali, and heating for reaction to obtain a compound 1.
Preferably, in step 1, the solvent used for the reaction is one or more of toluene, dichloromethane, dichloroethane, THF, acetonitrile, and ethyl acetate.
Preferably, in step 1, the catalyst is one or more of anhydrous aluminum trichloride, anhydrous zinc chloride, anhydrous ferric trichloride, concentrated sulfuric acid and boron trifluoride diethyl etherate.
Preferably, in step 1, the molar ratio of the R (+) -alpha-phenylethylamine to the catalyst to the bromine is 1: 1-3: 1-3; the reaction time is 0.5-5h, preferably 1-2 h; the reaction temperature is-20 to 20 ℃, preferably-5 to 5 ℃.
Preferably, in step 2, the catalyst is one or more of zinc chloride, ferric chloride and cuprous chloride.
Preferably, in step 2, the molar ratio of the compound 2, hydrochloric acid, paraformaldehyde and catalyst is 1: 1-10: 1-3: 0.05-0.5.
Preferably, in the step 2, the reaction time is 2-10h, preferably 5-6 h; the reaction temperature is 20-100 ℃, and preferably 55-65 ℃.
Preferably, in step 3, the solvent is one or more of water, methanol, ethanol, acetonitrile, acetone, DMF, ethyl acetate, toluene and xylene; the alkali is one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium methoxide, sodium ethoxide, sodium tert-butoxide and sodium hydride.
Preferably, in step 3, the molar ratio of compound 3 to base is 1: 1 to 4.
Preferably, in step 3, the temperature of the reaction is 60 to 110 ℃, preferably 70 to 80 ℃; the reaction time is 10-20h, preferably 13-14 h.
Has the advantages that: the invention provides a novel synthesis method of a gatifloxacin intermediate (1R) -5-bromo-2, 3-dihydro-1-methyl-1H-isoindole, which has the advantages of simple reaction, short route, less three wastes, environmental friendliness, higher yield of each step, less waste of raw materials and reagents and particular suitability for industrial production.
Detailed Description
The present invention will be further described with reference to the following examples in order to provide a thorough understanding of the present invention. The experimental procedures used in the following examples are all conventional procedures unless otherwise specified. The materials and reagents used in the following examples are commercially available without specific reference
Example 1
Step 1, preparation of Compound 2
20.0g (0.165mol, 1.0eq) of R- (+) -1-phenylethylamine was dissolved in 110ml of dichloromethane, cooled to 5 ℃ in an ice bath, and 30.8g (0.231mol, 1.4eq) of anhydrous aluminum chloride was added in portions and stirred for 30 minutes. Cooling to-5 deg.C, adding 29.0g (0.181mol, 1.1eq) of bromine dropwise in 2.5 hr at a temperature not higher than 5 deg.C, and reacting at 0 deg.C for 1.5 hr. The reaction mixture was added to 200g of ice and stirred for 10 minutes. The pH was adjusted to 13 with 25% sodium hydroxide solution, and the organic layer was separated and dried over anhydrous sodium sulfate. The distillation was carried out under reduced pressure (12mmHg) and the fractions at 125 ℃ and 122 ℃ were collected. The yield thereof was found to be 89.1%.
1H NMR(400MHz,CDCl3)δ(ppm):7.53(d,2H),7.29(d,2H),4.10(q,1H),1.68(br s,2H),1.37(d,3H)。
Step 2, preparation of Compound 3
25.0g (0.125mol, 1.0eq) of Compound 2 was added to 120ml of dilute hydrochloric acid (20%, 0.657mol, 5.3eq), and the mixture was stirred at 50 ℃ for 1 hour. The temperature was reduced to 20 ℃ and 3.4g (0.025mol, 0.2eq) of zinc chloride and 4.11g (0.137mol, 1.1eq) of paraformaldehyde were added in succession. After the addition, the temperature is raised to 65 ℃ for reaction for 6h, the temperature is lowered to 10 ℃, and 25% sodium hydroxide solution is slowly added dropwise to adjust the pH value to 10. Extraction was performed by adding dichloromethane (50ml x 2), and dichloromethane was combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The yield thereof was found to be 76.9%.
1H NMR(400MHz,CDCl3)δ(ppm):7.53(d,2H),7.41(s,1H),4.98(s,2H),4.55(q,1H),1.75(br s,2H),1.41(d,3H)。
Step 3, preparation of Compound 1
45.5g (0.183mol, 1.0eq) of the compound was dissolved in 430ml of acetonitrile, 40.5g (0.293mol, 1.6eq) of light potassium carbonate was added, and the reaction was allowed to proceed at 80 ℃ for 13 hours. Cooling to 20 ℃, filtering, and washing the solid with a small amount of acetonitrile. The filtrate was concentrated to a volume of about 100ml, and 300ml of water was added and stirred for 1 h. Suction filtration and washing of the filter cake with water (30 ml. times.3). Recrystallizing the ethyl acetate to obtain a white solid. The yield thereof was found to be 81.8%.
1H NMR(400MHz,CDCl3)δ(ppm):δ7.49-7.36(d,2H),7.07(d,1H),4.66-4.60(m,1H),4.22-4.15(m,2H),2.33(br s,1H),1.42(d,3H)。
Example 2
Step 1, preparation of Compound 2
20.0g (0.165mol, 1.0eq) of R- (+) -1-phenylethylamine was dissolved in 110ml of dichloromethane, cooled to 5 ℃ in an ice bath, and 31.5g (0.231mol, 1.4eq) of anhydrous zinc chloride was added in portions and stirred for 30 minutes. Cooling to-5 deg.C, adding 29.0g (0.181mol, 1.1eq) of bromine dropwise in 2.5 hr at a temperature not higher than 5 deg.C, and reacting at 0 deg.C for 1.5 hr. The reaction mixture was added to 200g of ice and stirred for 10 minutes. The pH was adjusted to 13 with 25% sodium hydroxide solution, and the organic layer was separated and dried over anhydrous sodium sulfate. The distillation was carried out under reduced pressure (12mmHg) and the fractions at 125 ℃ and 122 ℃ were collected. The yield thereof was found to be 72.6%.
1H NMR(400MHz,CDCl3)δ(ppm):7.53(d,2H),7.29(d,2H),4.10(q,1H),1.68(br s,2H),1.37(d,3H)。
Step 2, preparation of Compound 3
25.0g (0.125mol, 1.0eq) of Compound 2 was added to 120ml of dilute hydrochloric acid (20%, 0.657mol, 5.3eq), and the mixture was stirred at 50 ℃ for 1 hour. The temperature was reduced to 20 ℃ and 3.4g (0.025mol, 0.2eq) of zinc chloride and 7.51g (0.250mol, 2.0eq) of paraformaldehyde were added in succession. After the addition, the temperature is raised to 65 ℃ for reaction for 6h, the temperature is lowered to 10 ℃, and 25% sodium hydroxide solution is slowly added dropwise to adjust the pH value to 10. Extraction was performed by adding dichloromethane (50ml x 2), and dichloromethane was combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The yield thereof was found to be 75.1%.
1H NMR(400MHz,CDCl3)δ(ppm):7.53(d,2H),7.41(s,1H),4.98(s,2H),4.55(q,1H),1.75(br s,2H),1.41(d,3H)。
Step 3, preparation of Compound 1
45.5g (0.183mol, 1.0eq) of the compound was dissolved in 430ml of DMF, and 40.5g (0.293mol, 1.6eq) of light potassium carbonate was added, and the reaction was allowed to proceed at 80 ℃ for 13 hours. Cooling to 20 ℃, filtering, and washing the solid with a small amount of acetonitrile. The filtrate was concentrated to a volume of about 100ml, and 300ml of water was added and stirred for 1 h. Suction filtration and washing of the filter cake with water (30 ml. times.3). Recrystallizing the ethyl acetate to obtain a white solid. The yield thereof was found to be 84.3%.
1H NMR(400MHz,CDCl3)δ(ppm):δ7.49-7.36(d,2H),7.07(d,1H),4.66-4.60(m,1H),4.22-4.15(m,2H),2.33(br s,1H),1.42(d,3H)。
Claims (10)
1. A synthesis method of a gatifloxacin intermediate (1R) -5-bromo-2, 3-dihydro-1-methyl-1H-isoindole is characterized by comprising the following steps:
step 1: taking R (+) -alpha-phenylethylamine as a raw material and Lewis acid as a catalyst, and carrying out bromine bromination reaction to obtain a compound 2;
step 2: placing the compound 2 in a solvent, adding hydrochloric acid, paraformaldehyde and a catalyst, and carrying out chloromethylation reaction to obtain a compound 3;
and step 3: dissolving the compound 3 in a solvent, adding alkali, and heating for reaction to obtain a compound 1.
2. The synthesis method of the gatifloxacin intermediate (1R) -5-bromo-2, 3-dihydro-1-methyl-1H-isoindole according to claim 1, wherein the solvent used in the reaction in step 1 is one or more of toluene, dichloromethane, dichloroethane, THF, acetonitrile and ethyl acetate.
3. The synthesis method of the intermediate (1R) -5-bromo-2, 3-dihydro-1-methyl-1H-isoindole of the gatifloxacin as claimed in claim 1, wherein in the step 1, the catalyst is one or more of anhydrous aluminum trichloride, anhydrous zinc chloride, anhydrous ferric trichloride, concentrated sulfuric acid and boron trifluoride diethyl etherate.
4. The synthesis method of the gatifloxacin intermediate (1R) -5-bromo-2, 3-dihydro-1-methyl-1H-isoindole according to claim 1, wherein in the step 1, the molar ratio of the R (+) - α -phenylethylamine to the catalyst to the bromine is 1: 1-3: 1-3; the reaction time is 0.5-5h, preferably 1-2 h; the reaction temperature is-20 to 20 ℃, preferably-5 to 5 ℃.
5. The synthesis method of the gatifloxacin intermediate (1R) -5-bromo-2, 3-dihydro-1-methyl-1H-isoindole according to claim 1, wherein the catalyst is one or more of zinc chloride, ferric chloride and cuprous chloride in the step 2.
6. The synthesis method of the gatifloxacin intermediate (1R) -5-bromo-2, 3-dihydro-1-methyl-1H-isoindole according to claim 1, wherein in the step 2, the molar ratio of the compound 2, hydrochloric acid, paraformaldehyde and the catalyst is 1: 1-10: 1-3: 0.05-0.5.
7. The synthesis method of the gatifloxacin intermediate (1R) -5-bromo-2, 3-dihydro-1-methyl-1H-isoindole according to claim 1, wherein the reaction time in step 2 is 2-10H, preferably 5-6H; the reaction temperature is 20-100 ℃, and preferably 55-65 ℃.
8. The synthesis method of the gatifloxacin intermediate (1R) -5-bromo-2, 3-dihydro-1-methyl-1H-isoindole according to claim 1, wherein the solvent is one or more of water, methanol, ethanol, acetonitrile, acetone, DMF, ethyl acetate, toluene, and xylene in step 3; the alkali is one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium methoxide, sodium ethoxide, sodium tert-butoxide and sodium hydride.
9. The synthesis method of the gatifloxacin intermediate (1R) -5-bromo-2, 3-dihydro-1-methyl-1H-isoindole according to claim 1, wherein in the step 3, the molar ratio of the compound 3 to the base is 1: 1 to 4.
10. The synthesis method of the gatifloxacin intermediate (1R) -5-bromo-2, 3-dihydro-1-methyl-1H-isoindole according to claim 1, wherein the reaction temperature in step 3 is 60-110 ℃, preferably 70-80 ℃; the reaction time is 10-20h, preferably 13-14 h.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016121959A1 (en) * | 2015-01-30 | 2016-08-04 | 富士フイルム株式会社 | Method for producing isoindoline compound or salt thereof, novel isoindoline compound and salt thereof |
| CN106957255A (en) * | 2017-03-28 | 2017-07-18 | 上海馨远医药科技有限公司 | Methylisoindoline of 5 bromines of one kind (R) N Boc 1 and its preparation method and application |
| CN110938028A (en) * | 2019-12-09 | 2020-03-31 | 南京杰运医药科技有限公司 | Preparation method of (1R) -5-bromo-2, 3-dihydro-1-methyl-1H-isoindole |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016121959A1 (en) * | 2015-01-30 | 2016-08-04 | 富士フイルム株式会社 | Method for producing isoindoline compound or salt thereof, novel isoindoline compound and salt thereof |
| CN106957255A (en) * | 2017-03-28 | 2017-07-18 | 上海馨远医药科技有限公司 | Methylisoindoline of 5 bromines of one kind (R) N Boc 1 and its preparation method and application |
| CN110938028A (en) * | 2019-12-09 | 2020-03-31 | 南京杰运医药科技有限公司 | Preparation method of (1R) -5-bromo-2, 3-dihydro-1-methyl-1H-isoindole |
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