CN111620866A - Cis-7, 7-difluoro-hexahydro-1H pyrrolo [3,4-c ] pyridine derivative and preparation method thereof - Google Patents
Cis-7, 7-difluoro-hexahydro-1H pyrrolo [3,4-c ] pyridine derivative and preparation method thereof Download PDFInfo
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract
The invention discloses a cis-7, 7-difluoro-hexahydro-1H-pyrrolo [3,4-c ] pyridine derivative and a preparation method thereof, wherein the preparation method comprises the following steps: taking N-substituent-3-oxo-3, 6-dihydro-2H-pyridine (compound II) as a raw material, and carrying out 3+2 cycloaddition reaction with a compound III (N- (methoxymethyl) -N- (trimethylsilylmethyl) benzylamine) to obtain a compound IV; reacting the compound IV with a fluorinating reagent to obtain a compound V; finally, the compound V is subjected to debenzylation protecting group to obtain the cis-7, 7-difluoro-hexahydro-1H-pyrrolo [3,4-c ] pyridine derivative (compound I).
Description
Technical Field
The invention relates to the field of synthesis of drug intermediates, in particular to a cis-7, 7-difluoro-hexahydro-1H-pyrrolo [3,4-c ] pyridine derivative and a preparation method thereof.
Background
Patent WO2018050684 discloses that compound VI, which is useful as a Menin/MLL protein/protein interaction inhibitor, for the treatment of myelodysplastic syndrome (MDS) and diabetes. Patent WO2018045907 discloses compound VII, a novel 2-acylaminothiazole derivative, which can be used for the treatment and/or prevention of diseases mediated by thrombopoietin receptor. Wherein the compound VIII (octahydro-1H-pyrrolo [3,4-c ] pyridine) is a key intermediate for synthesizing the compound VI and the compound VII.
octahydro-1H-pyrrolo [3,4-c ] pyridines and related derivatives have wide application in medicinal chemistry and organic synthesis. Generally, fluorine atoms are introduced into the compound to improve the lipophilicity and metabolic stability of the molecule and improve the pharmacodynamic activity of the biological medicine, so that the cis-7, 7-difluoro-hexahydro-1H-pyrrolo [3,4-c ] pyridine derivative can be applied to the development of various medicines and the molecular design, and has wide market prospect.
Disclosure of Invention
The purpose of the invention is as follows: the invention aims to provide a cis-7, 7-difluoro-hexahydro-1H-pyrrolo [3,4-c ] pyridine derivative and a preparation method thereof, and mainly solves the technical blank of the existing preparation method. The synthesis method has the advantages of easily obtained raw materials, convenient operation, easy control of reaction and higher yield.
Taking N-substituent-3-oxo-3, 6-dihydro-2H-pyridine (compound II) as a raw material, and carrying out 3+2 cycloaddition reaction with a compound III (N- (methoxymethyl) -N- (trimethylsilylmethyl) benzylamine) to obtain a compound IV; reacting the compound IV with a fluorinating reagent to obtain a compound V; finally, the compound V is subjected to debenzylation protecting group to obtain the cis-7, 7-difluoro-hexahydro-1H-pyrrolo [3,4-c ] pyridine derivative (compound I).
In one aspect, the present invention discloses compounds of structural formula (I):
wherein: r1Is tert-butyloxycarbonyl, hydrogen, benzyloxycarbonyl or benzoyl.
In another aspect, the invention discloses a method of preparing compound I, comprising:
wherein: r2Is tert-butyloxycarbonyl, benzyloxycarbonyl or benzoyl;
when R is2In the case of tert-butoxycarbonyl or benzoyl, the reaction of the step from compound V to compound I takes place in the presence of a catalyst/hydrogen, R1Is tert-butyloxycarbonyl or benzoyl;
when R is2In the case of benzyloxycarbonyl:
a) the step of reacting the compound V to the compound I is carried out under the condition of chloroformic acid-1-chloroethyl ester, R1Is benzyloxycarbonyl;
b) the step of reacting the compound V to the compound I, R1Is hydrogen;
preferably, in the step of preparing the compound IV from the compound II and the compound III, the molar ratio of the compound II to the compound III is 1: 1-1: 5;
preferably, in the step of preparing the compound IV by using the compound II and the compound III, the reaction temperature ranges from-10 ℃ to 50 ℃;
preferably, during the step of preparing the compound IV from the compound II and the compound III, trifluoroacetic acid is added; the molar ratio of the compound II to the compound III to the trifluoroacetic acid is 1: 1-5: 0.1-0.5;
preferably, in the step of preparing compound V from compound IV, the fluorinating agent is diethylaminosulfur trifluoride, diethylaminosulfur trifluoride tetrafluoroborate, [ bis (2-methoxyethyl) amine ] sulfur trifluoride;
preferably, in the step of preparing the compound V from the compound IV, the molar ratio of the compound IV to the fluorinating reagent is 1: 1-1: 5; the reaction temperature is-78-20 ℃;
preferably, when the step of reacting compound V to compound I occurs under catalyst/hydrogen conditions, the catalyst is palladium on carbon or palladium on carbon hydroxide;
preferably, the step of reacting compound V to compound I occurs under catalyst/hydrogen conditions, with a hydrogen pressure in the range of 1atm to 10 atm; the reaction temperature range is 10-50 ℃;
preferably, when R is2The step of reacting the compound V to the compound I under the chloroformic acid-1-chloroethyl ester condition is performed at the reaction temperature of 0-60 ℃ for benzyloxycarbonyl.
Advantageous effects
The invention provides a simple, convenient and effective synthetic route for the first time, the cis-7, 7-difluoro-hexahydro-1H-pyrrolo [3,4-c ] pyridine derivative is obtained by synthesis, the technical blank of the preparation method of the cis-7, 7-difluoro-hexahydro-1H-pyrrolo [3,4-c ] pyridine derivative is made up, the reaction condition is mild, the operation is simple and convenient, and the rapid preparation in a laboratory can be realized.
Abbreviations for the reagents referred to in the specification are as follows:
DAST: diethylaminosulfur trifluoride;
BAST: [ bis (2-methoxyethyl) amine ] sulfur trifluoride;
TFA: trifluoroacetic acid;
DCM: dichloromethane;
MeOH: methanol;
EtOH: ethanol;
PE: petroleum ether;
EA: and (3) ethyl acetate.
Detailed Description
The present invention will be further illustrated by the following specific examples, which are carried out on the premise of the technical scheme of the present invention, and it should be understood that these examples are only for illustrating the present invention and are not intended to limit the scope of the present invention.
Example 1
Preparation of Compound IV-1
Adding the compound II-1(18.00g, 91.26mmol, 1.0eq.) and the compound III (21.67g, 91.26mmol, 1.0eq.) into acetonitrile (200mL), heating to 40-50 ℃, reacting for 16h, and TLC shows that the raw materials are reacted completely. And (3) performing column chromatography purification (PE/EA elution) on the reaction liquid to obtain 12.00g of a yellow oily compound IV-1 with the yield of 40%.1HNMR(400MHz，CDCl3)(ppm)：7.32-7.26(m，5H)，4.13-4.03(m，2H)，3.98(m，1H)，3.76-3.54(m，2H)，3.17-3.12(m，1H)，2.99-2.87(m，3H)，2.77-2.72(m，2H)，2.39(m，1H)，1.49(s，9H)。
Preparation of Compound V-1
Compound IV-1(12.00g, 36.32mmol, 1.0eq.) was dissolved in DCM (200mL), cooled to-78 deg.C and added in portionsDAST tetrafluoroborate (33.27g, 145.27mmol, 4.0eq.) was added and the temperature was raised to 20 ℃ naturally for 16h, and TLC showed the end of the reaction. The reaction solution was washed with water, dried, made into sand, and purified by column chromatography (PE/EA elution) to give 4.50g of compound V-1 as a white solid with a yield of 35%.1HNMR(400MHz，CDCl3)(ppm)：7.33-7.26(m，5H)，3.76-3.62(m，5H)，3.38-3.32(m，1H)，2.83-2.68(m，4H)，2.61(m，1H)，2.42(m，1H)，1.49(s，9H)。
Preparation of Compound I-1
Compound V-1(4.5g, 12.77mmol, 1.0eq.) and 10% palladium on carbon (1.50 g) were added to MeOH (50mL) and the reaction was stirred for 16h at 50 deg.C under a hydrogen atmosphere and TLC indicated that the starting material was reacted. The reaction was filtered, concentrated to sand and purified by column chromatography (DCM/MeOH) to give 2.74g of white solid I-1 in 81.8% yield: 98 percent.1HNMR(400MHz，CDCl3)(ppm)：3.68-3.62(m，3H)，3.32-3.10(m，5H)，2.83-2.78(m，1H)，2.64-2.56(m，2H)，1.47(s，9H)；(ESI-TOF)m/z：[M+H]+calcd for C12H20F2N2O2：262；found：263。
Example 2
Preparation of Compound IV-2
Compound II-2(21.09g, 91.26mmol, 1.0eq.) and compound III (21.67g, 456.3mmol, 5.0eq.) were added to DCM (200mL), trifluoroacetic acid (1.04g, 9.126mmol, 0.1eq.) was added dropwise at-10 ℃, the reaction was stirred at 0 ℃ for 5h, TLC showed the starting materials were reacted. And (3) performing column chromatography purification (PE/EA elution) on the reaction liquid to obtain 19.96g of a compound IV-2 which is yellow oily matter, wherein the yield is 60%.1HNMR(400MHz，CDCl3)(ppm)：7.19(s，5H)，7.14-7.16(m，5H)，5.34(s，2H)4.13-4.03(m，2H)，3.62(s，2H)，2.92(s，2H)，2.49(s，2H)，2.43-2.44(m，2H)，2.21(s，2H)。
Preparation of Compound V-2
Compound IV-2(19.00g, 52.13mmol, 1.0eq.) was dissolved in DCM (200mL), cooled to-40 deg.C, DAST (8.40g, 52.13mmol, 1.0eq.) was added in portions, and after addition was complete, the reaction was stirred at 0 deg.C for 8h, and TLC indicated that the starting material was complete. The reaction solution was washed with water, dried, made into sand, and purified by column chromatography (PE/EA elution) to give 9.27g of compound V-2 as a yellow solid with a yield of 46%.
Preparation of Compound I-2
Mixing compound V-2(9.01g, 23.29mmol, 1.0eq.) with 10% Pd (OH)21.0 g/C, EtOH (50mL) was added, and the reaction was stirred at 10 ℃ under 5atm hydrogen atmosphere for 10h, and TLC showed the completion of the reaction. The reaction was filtered, concentrated to sand and purified by column chromatography (DCM/MeOH) to give 2.57g of white solid I-2 in 68.3% yield, purity: 98 percent.1HNMR(400MHz，CDCl3)(ppm)：3.06-3.04(m，2H)，2.75-2.68(m，6H)，2.13-2.11(m，1H)，2.01-2.03(m，2H)，1.81-1.83(m，1H)；(ESI-TOF)m/z：[M+H]+calcd for C7H12F2N2：162；found：163。
Example 3
Preparation of Compound IV-1
Compound II-1(18.00g, 91.26mmol, 1.0eq.) and compound III (84.53g, 365.04mmol, 4.0eq.) were added to acetonitrile (200mL), the reaction was stirred at room temperature for 18h, and TLC showed the starting material was reacted. And (3) performing column chromatography purification (PE/EA elution) on the reaction liquid to obtain 13.20g of a compound IV-1 which is yellow oily matter, wherein the yield is 44%.1HNMR(400MHz，CDCl3)(ppm)：7.32-7.26(m，5H)，4.13-4.03(m，2H)，3.98(m，1H)，3.76-3.54(m，2H)，3.17-3.12(m，1H)，2.99-2.87(m，3H)，2.77-2.72(m，2H)，2.39(m，1H)，1.49(s，9H)。
Preparation of Compound V-1
Dissolving compound IV-1(12.00g, 36.32mmol, 1.0eq.) in DCM (200mL), cooling to-78 deg.C, adding DAST (17.56g, 108.95mmol, 3.0eq.) in portions, after adding, naturally heating to 20 deg.C, reacting for 16h, TLC shows that the raw materials are reacted completely. Reaction solutionWashing with water, drying, making sand, and purifying by column chromatography (PE/EA leaching) to obtain compound V-1 as white solid 4.90g with yield 38.3%.1HNMR(400MHz，CDCl3)(ppm)：7.33-7.26(m，5H)，3.76-3.62(m，5H)，3.38-3.32(m，1H)，2.83-2.68(m，4H)，2.61(m，1H)，2.42(m，1H)，1.49(s，9H)。
Preparation of Compound I-1
Mixing compound V-1(4.5g, 12.77mmol, 1.0eq.) with 10% Pd (OH)21.01 g/C, MeOH (50mL), 10atm hydrogen at 15 deg.C, stirring for 18h, TLC indicated the completion of the reaction. The reaction was filtered, concentrated to sand and purified by column chromatography (DCM/MeOH) to give 2.81g of a white solid I-1 in 83.8% yield: 98 percent.1HNMR(400MHz，CDCl3)(ppm)：3.68-3.62(m，3H)，3.32-3.10(m，5H)，2.83-2.78(m，1H)，2.64-2.56(m，2H)，1.47(s，9H)；(ESI-TOF)m/z：[M+H]+calcd for C12H20F2N2O2：262；found：263。
Example 4
Preparation of Compound IV-3
Compound II-3(18.00g, 89.52mmol, 1.0eq.) and compound III (63.76g, 268.55mmol, 3.0eq.) were added to DCM (300mL), trifluoroacetic acid (5.1g, 44.7mmol, 0.5eq.) was added dropwise at-10 ℃, the reaction was stirred at 20 ℃ for 16h, TLC showed the starting material was reacted. And (3) performing column chromatography purification (PE/EA elution) on the reaction liquid to obtain 15.86g of a compound IV-3 as a yellow oily substance, wherein the yield is 53.0%.
Preparation of Compound V-3
Compound IV-3(15.00g, 44.89mmol, 1.0eq.) was dissolved in DCM (200mL), cooled to-78 deg.C, BAST (49.65g, 224.44mmol, 5.0eq.) was added in portions, and after addition was complete, the reaction was stirred at 10 deg.C for 10h, and TLC indicated that the starting material was complete. The reaction solution was washed with water, dried, made into sand, and purified by column chromatography (PE/EA elution) to obtain compound V-3 as a white solid 8.79g with a yield of 55.1%.
Preparation of Compound I-3
Compound V-3(8.01g, 22.46mmol, 1.0eq.) and 10% Pd/C0.8 g were added to EA (50mL), stirred at 50 ℃ under 10atm hydrogen atmosphere for 8h, and TLC indicated that the starting material was reacted. The reaction was filtered, concentrated to sand and purified by column chromatography (DCM/MeOH) to give 3.99g of white solid I-3 in 66.7% yield: 98 percent.1HNMR(400MHz，CDCl3)(ppm)：7.44-7.95(m，5H)，3.65-3.67(m，2H)，3.28-3.31(m，2H)，2.68-2.73(m，2H)，2.11-2.20(m，2H)，1.98-2.01(m，1H)，2.01(s，2H)；(ESI-TOF)m/z：[M+H]+calcd for C14H16F2N2O2：266；found：267。
Example 5
Preparation of Compound I-4:
the compound V-2(9.01g, 23.29mmol, 1.0eq.) is dissolved in 100mL DCM, 1-chloroethyl chloroformate (3.33g, 23.29mmol, 1.05eq.) is added dropwise at 0-5 ℃, then the mixture is naturally warmed to room temperature and stirred for reaction for 4h, LC-MS detects that the reaction is complete, and DCM is removed by concentration under reduced pressure. Then 100mL of methanol is added, the reaction is stirred at 60 ℃ for 2h, the methanol is removed by concentration, a white solid is obtained, the white solid is dissolved in DCM, the pH value is adjusted to 7 by saturated sodium carbonate, the liquid is separated, the aqueous phase is extracted by DCM, the organic phase is combined, and the compound I-4 purified by sand column chromatography (DCM/MeOH) is concentrated to be 4.51g of yellow solid, the yield is 65.3%, and the purity: 98 percent. (ESI-TOF) m/z: [ M + H ]]+calcd for C15H18F2N2O2：296；found：297。
Claims (10)
1. A compound of structural formula (I):
wherein: r1Is tert-butyloxycarbonyl, hydrogen, benzyloxycarbonyl or benzoyl.
2. A process for the preparation of compound I according to claim 1, comprising:
wherein: r2Is tert-butyloxycarbonyl, benzyloxycarbonyl or benzoyl;
when R is2In the case of tert-butoxycarbonyl or benzoyl, the reaction of the step from compound V to compound I takes place in the presence of a catalyst/hydrogen, R1Is tert-butyloxycarbonyl or benzoyl;
when R is2In the case of benzyloxycarbonyl:
a) the step of reacting the compound V to the compound I is carried out under the condition of chloroformic acid-1-chloroethyl ester, R1Is benzyloxycarbonyl;
b) the step of reacting the compound V to the compound I, R1Is hydrogen.
3. The method of claim 2, wherein: in the step of preparing the compound IV from the compound II and the compound III, the molar ratio of the compound II to the compound III is 1: 1-1: 5.
4. The production method according to claim 2 or claim 3, characterized in that: in the step of preparing the compound IV from the compound II and the compound III, the reaction temperature ranges from-10 ℃ to 50 ℃.
5. The method of claim 4, wherein: in the step of preparing the compound IV from the compound II and the compound III, trifluoroacetic acid is added; the molar ratio of the compound II to the compound III to the trifluoroacetic acid is 1: 1-5: 0.1-0.5.
6. The method of claim 2, wherein: in the step of preparing the compound V from the compound IV, the fluorinating agent is diethylaminosulfur trifluoride, diethylaminosulfur trifluoride tetrafluoroborate, [ bis (2-methoxyethyl) amine ] sulfur trifluoride.
7. The production method according to claim 2 or claim 6, characterized in that: in the step of preparing the compound V from the compound IV, the molar ratio of the compound IV to the fluorinating reagent is 1: 1-1: 5; the reaction temperature range is-78-20 ℃.
8. The method of claim 2, wherein: the step of reacting compound V to compound I occurs under catalyst/hydrogen conditions, the catalyst being palladium on carbon or palladium on carbon hydroxide.
9. The production method according to claim 2 or claim 8, characterized in that: the step of reacting the compound V to the compound I under the condition of catalyst/hydrogen, wherein the hydrogen pressure ranges from 1atm to 10 atm; the reaction temperature range is 10-50 ℃.
10. The method of claim 2, wherein: when R is2The step of reacting the compound V to the compound I under the chloroformic acid-1-chloroethyl ester condition is performed at the reaction temperature of 0-60 ℃ for benzyloxycarbonyl.
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| WO2012019426A1 (en) * | 2010-08-09 | 2012-02-16 | 上海恒瑞医药有限公司 | Phthalazinone derivative, and preparation method and pharmaceutical use thereof |
| US20120136000A1 (en) * | 2008-07-23 | 2012-05-31 | Juan-Miguel Jimenez | Tri-cyclic pyrazolopyridine kinase inhibitors |
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| CN1425008A (en) * | 2000-01-24 | 2003-06-18 | 沃尼尔·朗伯公司 | 3-aminoquinazolin-2, 4-dione antibacterial agents |
| WO2002102793A2 (en) * | 2001-06-19 | 2002-12-27 | Warner-Lambert Company Llc | Quinazolinediones as antibacterial agents |
| US20080188452A1 (en) * | 2006-10-02 | 2008-08-07 | Altenbach Robert J | Macrocyclic Benzofused Pyrimidine Derivatives |
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