CN115894503A - Preparation method of azacyclopentane derivative - Google Patents

Preparation method of azacyclopentane derivative Download PDF

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CN115894503A
CN115894503A CN202211726651.XA CN202211726651A CN115894503A CN 115894503 A CN115894503 A CN 115894503A CN 202211726651 A CN202211726651 A CN 202211726651A CN 115894503 A CN115894503 A CN 115894503A
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何大荣
袁杰
卢竹青
司圣孟
陈越磊
赵浩英
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Hefei Nuoquan Pharmaceutical Co ltd
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Abstract

A preparation method of an azacyclopentane derivative comprises the following steps: taking proline hydrochloride as a raw material, and esterifying the L-proline hydrochloride or the D-proline hydrochloride to obtain a compound shown in a formula 3; reacting the compound shown in the formula 3 with epoxy chloropropane to obtain a compound shown in a formula 4S or 4R, carrying out cyclization reaction on the compound shown in the formula 4S or 4R to obtain a compound shown in a formula 5R or 5S, carrying out fluorination reaction on the compound shown in the formula 5R or 5S to obtain a compound shown in a formula 6, and reducing the compound shown in the formula 6 to obtain the azacyclopentane derivative shown in the formula 1. The method is a synthetic route starting from L-proline hydrochloride, the improved route only comprises 5 or 6 steps of reaction, raw materials are cheap and easy to obtain, and fluorination and reduction reactions with relatively high cost are also in the later stage of the route, so that the route has high value.

Description

Preparation method of azacyclopentane derivative
Technical Field
The invention relates to the technical field of chemical synthesis, in particular to a preparation method of an azacyclopentane derivative.
Background
In recent years, the compound ((2r, 7as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methanol, of the formula 1:
Figure BDA0004030297040000011
KRASG12D is the most common mutation of KARS, and is expressed in various cancer species such as pancreatic cancer, colorectal cancer, lung adenocarcinoma, bile duct cancer and the like to different degrees, and a brand-new selective non-covalent high-affinity KARSG12D inhibitor MRTX1133 which can be combined with KRASG12D mutants in an inactivated state and an activated state simultaneously is discovered. The compound shown in the formula 1 is used as a raw material in the design and synthesis of some bioactive compounds, such as a KRAS G12D inhibitor MRTX1133 of tumor, and has a more important function. However, the synthesis of compound 1 is difficult, and patent WO2022031678A1 reports a synthesis method using reagents such as ozone, dimethyl sulfide, DAST, and lithium aluminum hydride which are not friendly to process development, and the synthesis process is as follows:
Figure BDA0004030297040000012
recently, there is another document [ Organic Process Research & Development 2022,26 (10), 2839-2846 ] reporting an improved synthetic method of compound 1, but this synthetic route is also long and cumbersome to implement, and the specific Process is as follows:
Figure BDA0004030297040000021
in order to solve the problem of synthesis of the compound 1, it is necessary to develop a new preparation method with simple process and low synthesis cost.
Disclosure of Invention
The invention aims to provide a preparation method of an azacyclopentane derivative.
The technical scheme of the invention is as follows:
a process for the preparation of an azacyclopentane derivative comprising the steps of:
the structural formula of the azacyclopentane derivative is shown as a formula 1:
Figure BDA0004030297040000022
s1, taking L-proline hydrochloride or D-proline hydrochloride as a raw material, esterifying the L-proline hydrochloride or the D-proline hydrochloride to obtain a compound of a formula 3 or an enantiomer thereof,
Figure BDA0004030297040000023
wherein R is alkyl;
s2, reacting the compound shown in the formula 3 with (S) -epichlorohydrin to obtain a compound shown in the formula 4S, or preparing an enantiomer of the compound shown in the formula 4S from an enantiomer of the compound shown in the formula 3;
Figure BDA0004030297040000031
s3, carrying out cyclization reaction on the compound of the formula 4S to obtain a compound of the formula 5R, or carrying out cyclization reaction on an enantiomer of the compound of the formula 4S to obtain an enantiomer of the compound of the formula 5R,
Figure BDA0004030297040000032
s4, carrying out fluorination reaction on the compound shown in the formula 5R to obtain a compound shown in the formula 6, or carrying out fluorination reaction on the enantiomer of the compound shown in the formula 5R to obtain the enantiomer of the compound shown in the formula 6,
Figure BDA0004030297040000033
and S5, reducing the compound of the formula 6 to obtain the compound of the formula 1, or reducing the enantiomer of the compound of the formula 6 to obtain the enantiomer of the compound of the formula 1.
In a further scheme, the compound shown in the formula 6 in the step S5 is subjected to saponification reaction to obtain a compound shown in a formula 7, and then the compound is reduced to obtain a compound shown in a formula 1; or saponifying the enantiomer of the compound of formula 6 in the step S5 to obtain the enantiomer of the compound of formula 7, reducing to obtain the enantiomer of the compound of formula 1,
Figure BDA0004030297040000041
in a further scheme, in the step S2, the compound shown in the formula 3 is reacted with (R) -epichlorohydrin to obtain a compound shown in the formula 4R, or an enantiomer of the compound shown in the formula 3 is reacted with (S) -epichlorohydrin to obtain an enantiomer of the compound shown in the formula 4R:
Figure BDA0004030297040000042
cyclizing the compound of the formula 4R to obtain the compound of the formula 5S, or cyclizing the enantiomer of the compound of the formula 4R to obtain the enantiomer of the compound of the formula 5S,
Figure BDA0004030297040000043
fluorination of the compound of formula 5S as described above to give the compound of formula 6, or fluorination of the enantiomer of the compound of formula 5S to give the enantiomer of the compound of formula 6.
Further, the esterification in the step S1 is to dissolve L-proline hydrochloride or D-proline hydrochloride in methanol, reduce the temperature to 0 ℃, and then slowly and dropwise add thionyl chloride into the reaction liquid for reaction.
Further, the reaction in the step S2 is to dissolve the compound of formula 3 in a protic solvent, cool the solution to 0 ℃, add an alkali and (S) or (R) -epichlorohydrin to carry out a reaction;
the protic solvent comprises water, methanol and ethanol;
the alkali comprises triethylamine, DBU, diisopropylethylamine, sodium bicarbonate, sodium carbonate and potassium carbonate;
the epichlorohydrin comprises R-epichlorohydrin and S-epichlorohydrin.
Further, in the step S3, the cyclization reaction is performed by dissolving the compound of formula 4S or 4R in dry tetrahydrofuran, cooling to-78 ℃, slowly adding alkali dropwise into the mixed solution, and reacting at-50 ℃ or below until the raw materials disappear; then pouring the reaction solution into citric acid aqueous solution, and using NaHCO 3 Adjusting the pH value to be alkalescent, finally extracting the water phase by DCM and MeOH according to the volume ratio of 5;
the solvent comprises tetrahydrofuran, methyl tertiary ether, 2-methyl tetrahydrofuran, toluene and dichloromethane; wherein the base comprises lithium diisopropylamide, liHMDS, KHMDS, and isopropyl magnesium chloride.
In a further scheme, the fluorination reaction in the step S4 means that the compound shown in the formula 5R or 5S is dissolved in a solvent, and the temperature of the reaction liquid is reduced to 0 ℃; then respectively adding a fluorination reagent into the reaction liquid; naturally heating the reaction solution to room temperature for reaction;
the solvent includes but is not limited to tetrahydrofuran, methyl tertiary ether, 2-methyl tetrahydrofuran, toluene, methylene chloride; the fluorinating reagent comprises DAST, a combination of trifluoromethanesulfonic anhydride-HF pyridine solution, a combination of trifluoromethanesulfonic anhydride-HF triethylamine solution and perfluorobutanesulfonyl fluoride.
Further, the reduction in the step S5 is to dissolve the compound of the formula 6 in a solvent, cool the reaction solution to 0 ℃, add a reducing agent into the reaction solution, stir the reaction, quench the reaction with ice water after the reaction is finished, and obtain the compound of the formula 1 by filtering, concentrating, extracting and purifying;
the solvent comprises tetrahydrofuran, methyl tertiary ether, 2-methyl tetrahydrofuran and toluene;
the reducing agent comprises lithium aluminum hydride, lithium borohydride and Red-Al.
Further, adding a NaOH aqueous solution with the mass concentration of 20% into the saponification reaction, and adjusting the pH of the reaction solution to 2-3 by using acid after the reaction is finished;
the reduction is carried out by adding a reducing agent, and the reducing agent is borane.
The chemical reaction process of the application is as follows:
Figure BDA0004030297040000061
the synthesis route starting from the L-proline hydrochloride is provided, the improvement route only comprises 5 or 6 steps of reaction, raw materials are cheap and easy to obtain, and fluorination and reduction reactions with relatively high cost are also in the later stage of the route, so that the route has high value.
The present invention can be carried out via intermediates (4 aS) and (5 aR) via the proline methyl ester route.
Figure BDA0004030297040000062
In addition, using the route of the epichlorohydrin enantiomer, the same compound of formula 1 can also be obtained via intermediates (4 aR) and (5 aS):
Figure BDA0004030297040000063
the main advantages of the invention include:
(a) The reagent needed by the method is cheap and the cost is low;
(b) The method has simple post-treatment operation;
(c) The method has the advantages of short reaction time, easy industrial production and the like.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of compound 5aS prepared in example 11;
FIG. 2 is a NMR spectrum of Compound 6a prepared in example 12.
Detailed Description
In order to facilitate the understanding of the technical solutions of the present invention for those skilled in the art, the technical solutions of the present invention will now be further described with reference to specific embodiments.
The invention is further illustrated with reference to specific embodiments. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight.
Example 1
Figure BDA0004030297040000071
Dissolving 2 (100g, 0.77mol) in methanol (500 mL), cooling to 0 ℃, slowly dropwise adding thionyl chloride (101g, 0.85mol) into the reaction liquid, reacting for 5h at room temperature, detecting the disappearance of the raw materials by TLC, and concentrating the reaction liquid in vacuum to obtain a product 3a (153.8 g). The intermediate prepared in this example was subjected to high resolution mass spectrometry HRMS detection analysis: m + H + Molecular formula C6H12NO2+, calculated 130.0863, measured 130.0868.
Example 2
Figure BDA0004030297040000072
3a (5g, 0.03mol) was dissolved in methanol (16 mL) and water (8 mL), and 1, 8-diazabicycloundecen-7-ene (DBU) (8.0 g, 0.06mol) and S-epichlorohydrin (5.5g, 0.06mol) were added to the reaction solution while cooling to 0 ℃. After reaction at room temperature for 6 hours and detection of disappearance of the starting material by TLC, ethyl acetate (25mL, 5V) was added to the reaction mixture, and the reaction mixture was washed with a saturated aqueous ammonium chloride solution (25 mL. Times.5). The aqueous phase was extracted with ethyl acetate (25 mL), the organic phases combined and the organic phase concentrated in vacuo to give 4aS (4.7g, 70%). The intermediate prepared in this example was subjected to high resolution mass spectrometry HRMS detection analysis: m + H + The molecular formula is C9H17ClNO3+, calculated 222.0891, measured 222.0899.
Example 3
Figure BDA0004030297040000081
3a (5 g, 0.03mol) was dissolved in methanol (16 mL) and water (8 mL), cooled to 0 deg.C, and triethylamine (6.1g, 0.06mol) and S-epichlorohydrin (5.5 g, 0.06mol) were added to the reaction solution. After the reaction was carried out at room temperature for 6h, disappearance of the starting material was detected by TLC, methyl tert-ether (25mL, 5V) was added to the reaction mixture, and the reaction mixture was washed with a saturated aqueous ammonium chloride solution (25 mL. Times.5). The aqueous phase was extracted with methyl tert-ether (25 mL), the organic phases were combined and the organic phase was concentrated in vacuo to give 4aS (5.3 g, 79%). The thin layer chromatography of the product was identical to that of example 2; the intermediate prepared in this example was subjected to high resolution mass spectrometry HRMS detection analysis: m + H + Molecular formula C9H17ClNO3+, calculated 222.0891, measured 222.0895.
Example 4
Figure BDA0004030297040000082
3a (5g, 0.03mol) was dissolved in ethanol (16 mL) and water (8 mL), and the temperature was reduced to 0 ℃ to add sodium bicarbonate (5.0 g, 0.06mol) and S-epichlorohydrin (6.0 g, 0.065mol) to the reaction solution. After reaction at room temperature for 6 hours and detection of disappearance of the starting material by TLC, ethyl acetate (25mL, 5V) was added to the reaction mixture, and the reaction mixture was washed with a saturated aqueous ammonium chloride solution (25 mL. Times.5). The aqueous phase was extracted with ethyl acetate (25 mL), the organic phases combined and the organic phase concentrated in vacuo to give 4aS (4.1g, 61%). The thin layer chromatography of the product was identical to that of example 2.
Example 5
Figure BDA0004030297040000083
4aS (76g, 0.38mol) was dissolved in dry tetrahydrofuran (380mL, 5V), the temperature was lowered to-78 ℃ and 1M LiHMDS (800mL, 0.8mol) was slowly added dropwise to the reaction solution. Reaction was carried out for 4h, TLC checked for disappearance of starting material, the reaction was poured into aqueous citric acid (15%, 1L), pH was adjusted to 8 with sodium carbonate, the aqueous phase was extracted with DCM: meOH =5 (400 mL. Times.5), the organic phases were combined, and the organic phase was concentrated under reduced pressure to give 5aR (54g, 76%). For the present embodimentPerforming high resolution mass spectrum HRMS detection and analysis on the prepared intermediate: m + H + The molecular formula is C9H16NO3+, calculated 186.1125, measured 186.1133.
Example 6
Figure BDA0004030297040000091
4aS (75.0 g, 0.38mol) was dissolved in dry tetrahydrofuran (380mL, 5V), the temperature was lowered to-78 ℃ and a THF solution of lithium diisopropylamide (0.65 mol) was slowly added dropwise to the reaction mixture. Reaction was carried out for 4h, TLC checked for disappearance of starting material, the reaction was poured into aqueous citric acid (15%, 1L), pH was adjusted to 8 with potassium carbonate, the aqueous phase was extracted with DCM: meOH =5 (400 mL. Times.5), the organic phases were combined, and the organic phase was concentrated under reduced pressure to give 5aR (58g, 81%). The thin layer chromatography of the product was identical to that of example 5; the intermediate prepared in this example was subjected to high resolution mass spectrometry HRMS detection analysis: m + H + The molecular formula is C9H16NO3+, calculated 186.1125, measured 186.1135.
Example 7
Figure BDA0004030297040000092
Dissolving 5aR (3 g, 0.016mol) in dichloromethane (15 mL), cooling the reaction solution to-78 deg.C, adding DAST (0.024 mol), reacting at room temperature for 12h, detecting by TLC, pouring the reaction solution into saturated ammonium chloride water solution, and adding NaHCO 3 The pH was adjusted to 8, the aqueous phase was extracted with DCM (30 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give 6a (1.2g, 40%). The intermediate prepared in this example was subjected to high resolution mass spectrometry HRMS detection analysis: m + H + The molecular formula is C9H15FNO2+, calculated value is 188.1081, and measured value is 188.1088.
Example 8
Figure BDA0004030297040000101
5aR (3 g, 0.016mol) was dissolved in tetrahydrofuran (15 mL), the temperature of the reaction solution was lowered to 0 ℃, trifluoromethanesulfonic anhydride (0.02 mol) was added to the reaction solution, stirring was carried out at 0 ℃ for 30min, then a solution of HF in pyridine (0.08 mol) was added, the reaction solution was stirred at 0 ℃ for 48h, then the reaction solution was poured into a saturated aqueous ammonium chloride solution and treated with NaHCO 3 The pH was adjusted to 8, the aqueous phase was extracted with ethyl acetate (30 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and column purified to give 6a (1.4g, 47%). The thin layer chromatography of the product was identical to that of example 7; the intermediate prepared in this example was subjected to high resolution mass spectrometry HRMS detection analysis: m + H + The molecular formula is C9H15FNO2+, calculated value is 188.1081, and measured value is 188.1088.
Example 9
Figure BDA0004030297040000102
6a (4 g, 0.021mol) was dissolved in tetrahydrofuran (20mL, 5V), the reaction solution was cooled to 0 ℃ and 1M LiAlH was added to the reaction solution 4 (32mL, 0.032mol) was stirred for 1h, TLC detected disappearance of starting material, quenched with ice water, filtered, the two-phase filtrate was concentrated, the aqueous phase was extracted with ethyl acetate (20 mL. Times.3), the organic phases were combined, concentrated to dryness under reduced pressure, and purified by column chromatography to give 1 (2.5g, 75%). The intermediate prepared in this example was subjected to high resolution mass spectrometry HRMS detection analysis: m + H + Molecular formula is C8H15FNO +, calculated 160.1132, measured 160.1139.
Example 10
Figure BDA0004030297040000103
3a (60g, 0.362mol) was dissolved in methanol (192 mL) and water (96 mL), cooled to 0 ℃, and triethylamine (73.1g, 0.724mol) and R-epichlorohydrin (66.98g, 0.724mol) were added to the reaction solution. After reaction at room temperature for 6 hours and TLC detection of disappearance of the starting material, ethyl acetate (300mL, 5V) was added to the reaction mixture, and the reaction mixture was washed with a saturated aqueous ammonium chloride solution (300 mL. Times.5). The aqueous phase was extracted with ethyl acetate (300 mL), the organic phases were combined,the organic phase was concentrated in vacuo to give 4aS60g (80%). The intermediate prepared in this example was subjected to high resolution mass spectrometry HRMS detection analysis: m + H + Molecular formula C9H17ClNO3+, calculated 222.0891, measured 222.0895.
Example 11
Figure BDA0004030297040000111
4aR (58g, 0.28mol) was dissolved in dry tetrahydrofuran (290mL, 5V), the temperature was lowered to-78 deg.C, and a THF solution of lithium diisopropylamide (0.35 mol) was slowly added dropwise to the reaction solution. Reaction was carried out for 4h under-50 ℃ and disappearance of starting material was detected by TLC, the reaction solution was poured into an aqueous citric acid solution (15%, 0.8L), pH was adjusted to 8 with sodium carbonate, the aqueous phase was extracted with DCM: meOH =5 (290 mL. Times.5), the organic phases were combined, and the organic phase was concentrated under reduced pressure to give 5aS (27.8g, 53%). The intermediate prepared in this example was subjected to high resolution mass spectrometry HRMS detection analysis: m + H + The molecular formula is C9H16NO3+, calculated 186.1125, measured 186.1135. The intermediate prepared in this example was subjected to 1 The obtained spectrum is a nuclear magnetic resonance hydrogen spectrum of the compound 5aS shown in figure 1 by H-NMR study to prove the structure.
Example 12
Figure BDA0004030297040000112
5aS (24g, 0.13mol) was dissolved in toluene (120mL, 5V), the temperature of the reaction solution was lowered to-78 ℃ and DAST (0.22 mol) was added to the reaction solution. The reaction solution was allowed to naturally warm to room temperature for reaction 12h, TLC detected disappearance of starting material, poured into saturated aqueous ammonium chloride solution, adjusted to pH 8 with aqueous sodium carbonate solution, the aqueous phase was extracted with DCM (200 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give 6a (5.75g, 24%). The thin layer chromatography of the product was identical to that of example 7; the intermediate prepared in this example was subjected to high resolution mass spectrometry HRMS detection analysis: m + H + The molecular formula is C9H15FNO2+, calculated value is 188.1081, and measured value is 188.1086. For the intermediates prepared in this exampleTo proceed with 1 H-NMR study, FIG. 2 is a hydrogen nuclear magnetic resonance spectrum of Compound 6a to confirm its structure.
Example 13
Figure BDA0004030297040000121
6a (0.10 mol) was dissolved in toluene (5 mL), the temperature of the reaction solution was lowered to 0 ℃ and Red-Al solution (0.15 mol) was added to the reaction solution. The reaction solution was stirred at room temperature for 10h, TLC was carried out to detect the disappearance of the starting material, the reaction solution was poured into a saturated aqueous ammonium chloride solution, the organic phase was separated, concentrated under reduced pressure, and purified by column chromatography to obtain the compound of formula 1 (75%). The thin layer chromatography of the product was identical to that of example 9; the intermediate prepared in this example was subjected to high resolution mass spectrometry HRMS detection analysis: m + H + The molecular formula is C8H15FNO +, calculated 160.1132, measured 160.1138.
Example 14
Figure BDA0004030297040000122
After dissolving 6a (0.10 mol) in methanol (2 mL), 20% sodium hydroxide solution was added to the solution, TLC detection of the disappearance of the starting material was performed, the reaction solution was adjusted to pH 2 to 3 with 2M HCl, concentrated, and the residue was purified by column chromatography to obtain 7 (80%). The intermediate prepared in this example was subjected to high resolution mass spectrometry HRMS detection analysis: M-H - The molecular formula is C8H11FNO2-, calculated value is 172.0779, and measured value is 172.0783.
Example 15
Figure BDA0004030297040000123
7 (0.10 mol) was dissolved in THF (3 mL), the temperature of the reaction solution was lowered to 0 ℃ and a borane solution in THF (0.2 mol) was added to the reaction solution. The reaction solution was stirred at room temperature for 1693 h, TLC was used to detect the disappearance of the starting material, the reaction solution was poured into saturated aqueous ammonium chloride solution, the organic phase was separated, concentrated under reduced pressure, and purified by column chromatography to give 1 (67%). Prepared for this examplePerforming high resolution mass spectrum HRMS detection and analysis on the intermediate: m + H + The molecular formula is C8H15FNO +, calculated 160.1132, measured 160.1138.
All documents mentioned in this application are incorporated by reference in this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims (9)

1. A preparation method of an azacyclopentane derivative is characterized in that: the method comprises the following steps:
the structural formula of the azacyclopentane derivative is shown as a formula 1:
Figure FDA0004030297030000011
s1, esterifying L-proline hydrochloride or D-proline hydrochloride serving as a raw material to obtain a compound shown in a formula 3 or an enantiomer thereof,
Figure FDA0004030297030000012
wherein R is alkyl;
s2, reacting the compound shown in the formula 3 with (S) -epichlorohydrin to obtain a compound shown in the formula 4S, or preparing an enantiomer of the compound shown in the formula 4S from an enantiomer of the compound shown in the formula 3;
Figure FDA0004030297030000013
s3, carrying out cyclization reaction on the compound of the formula 4S to obtain a compound of a formula 5R, or carrying out cyclization reaction on an enantiomer of the compound of the formula 4S to obtain an enantiomer of the compound of the formula 5R,
Figure FDA0004030297030000021
s4, carrying out fluorination reaction on the compound of the formula 5R to obtain a compound of a formula 6, or carrying out fluorination reaction on an enantiomer of the compound of the formula 5R to obtain an enantiomer of the compound of the formula 6,
Figure FDA0004030297030000022
and S5, reducing the compound of the formula 6 to obtain the compound of the formula 1, or reducing the enantiomer of the compound of the formula 6 to obtain the enantiomer of the compound of the formula 1.
2. The production method according to claim 1, characterized in that: in the step S5, the compound of the formula 6 is subjected to saponification reaction to obtain a compound of a formula 7, and then the compound of the formula 1 is obtained through reduction; or saponifying the enantiomer of the compound of formula 6 in the step S5 to obtain the enantiomer of the compound of formula 7, reducing to obtain the enantiomer of the compound of formula 1,
Figure FDA0004030297030000023
3. the method of claim 1, wherein: in step S2, the compound shown in the formula 3 is reacted with (R) -epichlorohydrin to obtain a compound shown in the formula 4R, or the enantiomer of the compound shown in the formula 3 is reacted with (S) -epichlorohydrin to obtain the enantiomer of the compound shown in the formula 4R:
Figure FDA0004030297030000031
cyclizing the compound of the formula 4R to obtain the compound of the formula 5S, or cyclizing the enantiomer of the compound of the formula 4R to obtain the enantiomer of the compound of the formula 5S,
Figure FDA0004030297030000032
fluorination of the compound of formula 5S as described above to give the compound of formula 6, or fluorination of the enantiomer of the compound of formula 5S to give the enantiomer of the compound of formula 6.
4. The method of claim 1, wherein: the esterification in the step S1 is to dissolve L-proline hydrochloride or D-proline hydrochloride in methanol, reduce the temperature to 0 ℃, and then slowly and dropwise add thionyl chloride into the reaction solution for reaction.
5. The method of claim 1, wherein: the reaction in the step S2 is to dissolve the compound shown in the formula 3 in a protic solvent, cool the solution to 0 ℃, add alkali and epichlorohydrin to react;
the protic solvent comprises water, methanol and ethanol;
the alkali comprises triethylamine, DBU, diisopropylethylamine, sodium bicarbonate, sodium carbonate and potassium carbonate;
the epichlorohydrin comprises R-epichlorohydrin and S-epichlorohydrin.
6. The production method according to claim 1, characterized in that: the cyclization reaction in the step S3 is to dissolve the compound shown in the formula 4S in dry tetrahydrofuran, reduce the temperature to-78 ℃, slowly drop alkali into the mixed solution, and keep the temperature below-50 ℃ for reaction until the raw materials disappear; then the reaction solution is poured into citric acid aqueous solution and NaHCO is used 3 Adjusting the pH value to be alkalescent, finally extracting the water phase by DCM and MeOH according to the volume ratio of 5;
the solvent comprises tetrahydrofuran, methyl tertiary ether, 2-methyl tetrahydrofuran, toluene and dichloromethane; wherein the base comprises lithium diisopropylamide, liHMDS, KHMDS, and isopropyl magnesium chloride.
7. The method of claim 1, wherein: the fluorination reaction in the step S4 is to dissolve the compound shown in the formula 5R in a solvent, and reduce the temperature of the reaction solution to 0 ℃; then respectively adding a fluorination reagent into the reaction liquid; naturally heating the reaction solution to room temperature for reaction;
the solvent includes but is not limited to tetrahydrofuran, methyl tertiary ether, 2-methyl tetrahydrofuran, toluene, methylene chloride; the fluorinating reagent comprises DAST, a combination of trifluoromethanesulfonic anhydride-HF pyridine solution, a combination of trifluoromethanesulfonic anhydride-HF triethylamine solution and perfluorobutanesulfonyl fluoride.
8. The method of claim 1, wherein: the reduction in the step S5 is to dissolve the compound shown in the formula 6 in a solvent, cool the reaction liquid to 0 ℃, add a reducing agent into the reaction liquid, stir the reaction, quench the reaction with ice water after the reaction is finished, and obtain the compound shown in the formula 1 through filtration, concentration, extraction and purification;
the solvent comprises tetrahydrofuran, methyl tertiary ether, 2-methyl tetrahydrofuran and toluene;
the reducing agent comprises lithium aluminum hydride, lithium borohydride and Red-Al.
9. The method of claim 2, wherein: adding a NaOH aqueous solution with the mass concentration of 20% into the saponification reaction, and adjusting the pH of the reaction solution to 2-3 by using acid after the reaction is finished;
the reduction is carried out by adding a reducing agent, and the reducing agent is borane.
CN202211726651.XA 2022-12-30 2022-12-30 Preparation method of azacyclopentane derivative Pending CN115894503A (en)

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