CN117603116A - Method for preparing chiral beta-lactam - Google Patents

Method for preparing chiral beta-lactam Download PDF

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Publication number
CN117603116A
CN117603116A CN202311644705.2A CN202311644705A CN117603116A CN 117603116 A CN117603116 A CN 117603116A CN 202311644705 A CN202311644705 A CN 202311644705A CN 117603116 A CN117603116 A CN 117603116A
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Prior art keywords
substrate
reaction
chiral
lactam
catalyst
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CN202311644705.2A
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Chinese (zh)
Inventor
吴璇
陆清
胡振宇
童麟
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Jiangsu Hansyn Pharmaceutical Co ltd
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Jiangsu Hansyn Pharmaceutical Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
    • B01J31/0235—Nitrogen containing compounds
    • B01J31/0244—Nitrogen containing compounds with nitrogen contained as ring member in aromatic compounds or moieties, e.g. pyridine

Abstract

The invention discloses a method for preparing chiral beta-lactam, which comprises the steps of adding an organic solvent, a substrate I and a proton sponge into a dry reaction bottle, then adding a catalyst III and a substrate II, controlling a heat preservation reaction at a certain temperature, and performing post-treatment to obtain a product IV. The method obtains the target product through a proper chiral catalyst, and has mild conditions and high chiral selectivity.

Description

Method for preparing chiral beta-lactam
Technical Field
The invention relates to a method for preparing chiral beta-lactam, in particular to a method for synthesizing chiral beta-lactam derivatives by asymmetric catalysis of a chiral catalyst.
Background
Beta-lactams are a class of organic compounds with a specific structure, the molecules of which contain a beta-lactam group, and the general structure of which is shown in the following formula.
Beta-lactams were not complex in their own right, were first synthesized by Staudinger in 1907, but were not of much interest at the time. However, penicillin has been found and confirmed to contain beta-lactam in the penicillin structure soon after that, and as antibiotics are developed, more and more antibiotics containing beta-lactam structure have been found and used, and the substances are more and more paid attention to.
As the use of β -lactam antibiotics increases, many bacteria are derivatized for resistance to antibiotics. The research shows that the drug resistance of the bacterial body is mainly due to the fact that beta-lactamase is generated in the bacterial body, and the beta-lactamase can catalyze the hydrolysis of beta-lactam, so that the beta-lactam drug is disabled. This requires us to develop new β -lactam antibiotics or β -lactam inhibitors (a class of compounds containing β -lactam structures that are able to inactivate β -lactamases).
In addition to the antibiotic field, beta-lactams have also found application in some non-antibiotic fields, such as protease inhibitors. Based on the above total factors, the organic synthesis of β -lactams is also of increasing interest.
The synthesis method of the beta-lactam structure mainly comprises the following steps:
staudinger reaction. The reaction is to generate beta-lactam by [2+2] cycloaddition reaction between ketene and imine
Amine, the most common method for synthesizing beta-lactam structures, has the following equation:
Gilman-Speteter reaction. The reaction is usually carried out by reacting imine with alpha-bromo ester under the action of zinc powder. The reaction essentially forms a ring after the enol and the imine are condensed to obtain a product, and the reaction equation is as follows:
kinugasa reaction. The reaction is to obtain a product through cycloaddition reaction of terminal alkyne and nitrone, and the reaction equation is as follows:
4. other reactions. The product is obtained mainly by constructing a suitable single molecular structure in the form of condensation of the molecular lactam into a ring. Although the reaction into a ring part is simple, the construction of the molecular structure is complex, and the applicability is small.
The synthesis of chiral beta-lactam structure by using Staudinger reaction mainly depends on two means, one is to install chiral prosthetic groups on imine or ketene raw materials, and the chiral prosthetic groups are induced by using a three-dimensional structure, and the method is effective but has complicated steps; the other is the control of the stereoselectivity of the reaction by means of chiral catalysts.
The group of the problem of the Lectka project in 2000 reported the first asymmetric catalysis of Staudinger reactions, using cinchona derivatives as chiral catalysts. The normal Staudinger reaction is generally carried out at room temperature without a catalyst because of the very high nucleophilicity of the imine. The Lectka subject group skillfully changes the reaction mode through polarity inversion, and realizes asymmetric catalysis of the reaction through steric hindrance of a catalyst. And the cinchona alkaloid derivative combined with the proton sponge can react with acyl chloride to generate corresponding ketene in situ, so that the selection of raw materials is further widened.
The Lectka group studied a series of cinchona derivatives, mainly the benzoate of cinchona and the benzamide structure of cinchona amine, and found that the benzamide structure of cinchona amine was slightly higher in reaction conversion rate, but had poorer ee selectivity and dr selectivity than the benzoate of cinchona. And an explanation is given in terms of spatial structure.
After the ketene is combined with the benzoate of cinchona alkaloid, the oxyanion is bound by hydrogen on nitrogen-bearing carbon, so that the whole ketene is compressed in a smaller space, and the chiral selectivity of further reaction becomes good. After the ketene is combined with the benzamide of cinchona amine, the oxyanion is bound by hydrogen on amide nitrogen, the structure is more extended, and the space for further reaction is larger, so that the chiral selectivity is poorer. Thus, the benzamide structure of cinchona-amine has better homology with the achiral bifunctional catalyst N- (2- (diethylamino) ethyl) benzamide, but the Lectka subject group does not take it as an important subject.
Although the chiral selectivity of the benzoate of cinchona alkaloid is better, the combination stability of the benzoate and the ketene substrate is low, and the space compactness is higher, so that the yield of the whole reaction is lower, the larger the R group of the ketene substrate is, the better the chiral selectivity is, the lower the yield is, and both cannot be considered.
In order to improve the conversion rate of the reaction, the Lectka subject group introduces a Lewis acid catalyst on the original basis to improve the reaction activity of the imine, even introduces Lewis acid catalysis with large steric hindrance, and improves the yield of the reaction on the basis of ensuring chiral selectivity. The yield and selectivity of the reaction are excellent, but the reaction system becomes more complicated. And the dosage of the two catalysts is large (10 mol percent), which is not beneficial to industrialization.
Disclosure of Invention
The invention aims to solve the problems of harsh synthesis process conditions, low selectivity of chiral reagents, large dosage and high production cost of the existing chiral beta-lactam derivatives, and provides a method for synthesizing chiral beta-lactam derivatives by asymmetric catalysis of a chiral catalyst, wherein the dosage of the catalyst is small, and the cost is greatly reduced. The molar yield of the method is above 70%, the chiral purity can reach above 99% ee at the highest, and the cis-trans selectivity is also above 90% dr. In addition, the reaction method has mild reaction conditions and reaction temperature of between 40 ℃ below zero and 40 ℃ and is very favorable for realizing industrial production.
The technical scheme of the invention is as follows:
a process for preparing chiral β -lactams comprising the steps of:
1) Adding an organic solvent and a substrate I into a dried reaction bottle, and controlling the reaction system at a certain temperature (-40 ℃ to 40 ℃) by using a proton sponge;
2) Adding a catalyst III and a substrate II into a reaction bottle under the protection of nitrogen, regulating the temperature (-40 ℃ to 40 ℃), and stirring for 2 to 12 hours under the heat preservation;
3) And after the reaction is finished, distilling the solvent under reduced pressure, and carrying out column chromatography on distillation residues to obtain a product IV.
The substrate II in the step 2) is N-Ts ethyl iminoacetate;
in step 2), the reaction temperature is preferably controlled at-20℃to 20 ℃.
The structure of the catalyst III in the step 2) is as follows:
wherein r1=3, 5- (CF) 3 ) 2 C 6 H 3 ；4-CF 3 C 6 H 4 ；4-FC 6 H 4 ；
The molar ratio of catalyst III to substrate I is between 0.02:1 and 0.10:1;
the organic solvent in the step 1) is selected from one or a mixture of more than one of the following: dichloromethane, chloroform, toluene.
The molar ratio of compound II to substrate I is between 1:1 and 2:1.
The chemical reaction equation of the invention is shown as follows:
wherein R is aryl; heteroaryl; ar (CH) 2 ) n -a group Ar represents an aryl or heteroaryl group, n=1-6;
the structure of the catalyst III is as follows:
wherein r1=3, 5- (CF) 3 ) 2 C 6 H 3 ；4-CF 3 C 6 H 4 ；4-FC 6 H 4 。
General preparation of catalyst III:
wherein r1=3, 5- (CF) 3 ) 2 C 6 H 3 ；4-CF 3 C 6 H 4 ；4-FC 6 H 4 。
Adding methanol into a flask, adding phenol containing substituent groups, squaric acid, heating and refluxing at 80 ℃ for 8-10 h, cooling, rotationally evaporating the solvent to obtain a solid crude product, and filtering and drying after column chromatography to obtain an intermediate.
The dried intermediate is weighed and added into a reaction bottle, methylene dichloride is added for stirring and dissolution, quinine amine is added at the temperature of 25 ℃, and the reaction mixture is stirred for 48 hours at room temperature. At the end of the reaction, the purified water was washed twice. The organic phase is dried by spinning, added with methanol and pulped for 0.5 hour, filtered and dried under reduced pressure to obtain the catalyst.
The principle of catalysis and chiral selectivity of the catalyst is as follows: the catalyst is matched with proton sponge to firstly react the substrate I in situ to generate corresponding ketene, then the catalyst is combined with the ketene, and the space structure of the catalyst enables the substrate II to react with the substrate I in one direction only, so that the chiral substitution product required by people is obtained.
The beneficial effects are that:
the invention selects an effective catalyst, the catalyst consumption is small, and the cost is greatly reduced. The molar yield of the method is above 70%, the chiral purity can reach above 99% ee at the highest, and the cis-trans selectivity is also above 90% dr. In addition, the reaction method has mild reaction conditions and reaction temperature of between 40 ℃ below zero and 40 ℃ and is very favorable for realizing industrial production.
Detailed Description
For a better understanding of the present invention, reference will be made in detail to the following examples, which are not intended to limit the scope of the invention, but are capable of numerous modifications and variations within the scope of the invention as will be apparent to those skilled in the art from the description herein.
General preparation method of catalyst:
wherein r1=3, 5- (CF) 3 ) 2 C 6 H 3 ；4-CF 3 C 6 H 4 ；4-FC 6 H 4
In a 100mL flask, methanol (40 mL) was added, followed by the addition of the substituent-containing phenol (R 1 -OH,20.5 mmol), squaric acid (2.32 g,20.5 mmol), reflux by heating at 80 ℃ for 8-10 h, cooling, rotary evaporating the solvent to obtain crude solid, column chromatography, filtering and drying to obtain intermediate.
The dried intermediate was weighed (1.0 mmol) and added to the reaction flask, 10ml of dichloromethane was added and dissolved with stirring, quinine amine was added at 25℃and the reaction mixture was stirred at room temperature for 48 hours. At the end of the reaction, 10ml of purified water was washed twice. The organic phase is dried by spinning, 5ml of methanol is added for pulping for 0.5 hour, and the catalyst is obtained by filtering and drying under reduced pressure.
Example 1
The reaction flask was ready for drying in advance and kept dry. Toluene (30 mL), phenylacetyl chloride (2.00 g,12.9 mmol) and proton sponge (3.10 g,14.2 mmol) were added separately to the reaction flask and cooled to-30 ℃. After the temperature reached, a solution of catalyst (0.81 g,1.29 mmol) and substrate II (3.30 g,12.9 mmol) in toluene (20 mL) was added dropwise. Stirring for 1 hour at controlled temperature, slowly heating to 0 ℃, stirring and reacting for 5 hours, and completely reacting. The solvent was removed under reduced pressure and the crude product was isolated by column chromatography and dried by spin-drying to give product IV (4.43 g. 92% yield, 96% ee,95:5 dr).
1H-NMR(400MHz,CDCl3):δ7.81-7.71(m,2H),7.44-7.25(m,7H),5.02(d,J＝8.0Hz,1H),4.89(d,J＝8.0Hz,1H),4.00(m,2H),2.34(s,3H),1.30(t,J＝8.0Hz,3H)。
Example 2
The reaction flask was ready for drying in advance and kept dry. Toluene (30 mL), p-methoxyphenylacetyl chloride (2.38 g,12.9 mmol) and proton sponge (3.10 g,14.2 mmol) were added separately to the reaction flask, and the temperature was reduced to-30 ℃. After the temperature reached, a solution of catalyst (0.81 g,1.29 mmol) and substrate II (3.30 g,12.9 mmol) in toluene (20 mL) was added dropwise. Stirring for 1 hour at controlled temperature, slowly heating to 10 ℃, stirring and reacting for 5 hours, and completely reacting. The solvent was removed under reduced pressure and the crude product was isolated by column chromatography and dried by spin-drying to give product IV (4.47 g. Yield 86%,99% ee,99:1 dr).
1H-NMR(400MHz,CDCl3):δ7.81-7.71(m,2H),7.44-7.30(m,4H),7.05-6.95(m,2H),5.02(d,J＝8.0Hz,1H),4.89(d,J＝8.0Hz,1H),4.00(m,2H),3.85(s,3H),2.34(s,3H),1.30(t,J＝8.0Hz,3H)。
Example 3
The reaction flask was ready for drying in advance and kept dry. Toluene (30 mL), phenylacetyl chloride (2.00 g,12.9 mmol) and proton sponge (3.10 g,14.2 mmol) were added separately to the reaction flask and cooled to-30 ℃. After the temperature reached, a solution of catalyst (0.81 g,1.29 mmol) and substrate II (3.30 g,12.9 mmol) in toluene (20 mL) was added dropwise. Stirring for 1 hour at controlled temperature, slowly heating to 0 ℃, stirring and reacting for 5 hours, and completely reacting. The solvent was removed under reduced pressure, and the crude product was isolated by column chromatography and dried by spin-drying to give product IV (4.33 g. Yield 90%,96% ee (ent), 95:5 dr).
Example 4
The reaction flask was ready for drying in advance and kept dry. Toluene (30 mL), phenylacetyl chloride (2.00 g,12.9 mmol) and proton sponge (3.10 g,14.2 mmol) were added separately to the reaction flask and cooled to-30 ℃. After the temperature reached, a solution of catalyst (0.73 g,1.29 mmol) and substrate II (3.30 g,12.9 mmol) in toluene (20 mL) was added dropwise. Stirring for 1 hour at controlled temperature, slowly heating to 0 ℃, stirring and reacting for 5 hours, and completely reacting. The solvent was removed under reduced pressure and the crude product was isolated by column chromatography and dried by spin-drying to give product IV (4.72 g. 98% yield, 90% ee,90:10 dr).

Claims (7)

1. A method for preparing chiral beta-lactam, which is characterized in that a substrate I and a substrate II react under the catalysis of a catalyst III to obtain a product, wherein the chemical reaction equation is as follows:
wherein R is aryl; heteroaryl; ar (CH) 2 ) n -a group Ar represents an aryl or heteroaryl group, n=1-6;
the structure of the catalyst III is as follows:
wherein r1=3, 5- (CF) 3 ) 2 C 6 H 3 ；4-CF 3 C 6 H 4 ；4-FC 6 H 4 。
2. A process for the preparation of chiral β -lactams according to claim 1, characterized in that it comprises the steps of:
1) Adding an organic solvent, a substrate I and a proton sponge into a reaction bottle, and controlling the temperature of a reaction system to be between 40 ℃ below zero and 40 ℃;
2) Adding a catalyst III and a substrate II into a reaction bottle under the protection of nitrogen, adjusting the temperature to be between 40 ℃ below zero and 40 ℃, and stirring for 2 to 12 hours under the heat preservation;
3) And after the reaction is finished, distilling the solvent under reduced pressure, and carrying out column chromatography on distillation residues to obtain a product IV.
3. A process for the preparation of chiral β -lactams according to claim 1, characterized in that the molar ratio of catalyst III to substrate I is between 0.02:1 and 0.10:1.
4. A process for the preparation of chiral β -lactams according to claim 1, characterized in that the substrate II is N-Ts ethyl iminoacetate.
5. A process for the preparation of chiral β -lactams according to claim 2, characterized in that the organic solvent is selected from one or a mixture of several of the following: dichloromethane, chloroform, toluene.
6. A process for the preparation of chiral β -lactams according to claim 2, characterized in that in step 1) the reaction temperature is controlled between-20 ℃ and 20 ℃.
7. A synthetic method for preparing chiral β -lactams according to claim 2, characterized in that the molar ratio of substrate II to substrate I is between 1:1 and 2:1.
CN202311644705.2A 2023-12-04 2023-12-04 Method for preparing chiral beta-lactam Pending CN117603116A (en)

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CN117603116A true CN117603116A (en) 2024-02-27

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