Phenylalanine glimepiride derivative and preparation method thereof

Abstract

The invention relates to a phenylalanine glimepiride derivative. The phenylalanine glimepiride derivative contains L-phenylalanine methyl ester and pharmaceutically acceptable reaction materials, the preparation method comprises the following steps: dissolving L-phenylalanine methyl ester in an organic solvent, adding phenyl chloroformate, adding alkali, reacting at room temperature for 0.5-6 hours, adding 1M diluted hydrochloric acid, extracting, and purifying to obtain the L-phenylalanine methyl ester. And dissolving the crude product 4-[2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-formamido) ethyl]-benzenesulfonamide (CAS: 119018-29-0) in an organic solvent, adding alkali, carrying out a reflux reaction for 2-12 hours, carrying out reduced pressure distillation to remove the solvent, adding ethyl acetate and a 1M sodium hydroxide aqueous solution (V / V = 1: 1), carrying out a reaction for 2-12 hours, and carrying out reduced pressure distillation to obtain the 4-[2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-formamido) ethyl]-benzenesulfonamide. The preparation method comprises the following steps: adding the phenylalanine and the glimepiride into a reaction kettle, stirring to react for 0.5-3 hours, separating liquid, adjusting the pH value of a water phase to 2-3 by using concentrated hydrochloric acid, stirring overnight, filtering to obtain a white solid, and drying to obtain the phenylalanine glimepiride derivative. The method has the advantages of simple operation, high yield, common reagents, and suitableness for large-scale preparation.

Description

Technical Field

[0001] The invention relates to the technical field of synthesis of phenylalanine glimepiride derivatives, in particular to phenylalanine glimepiride derivatives and preparation methods thereof. Background Art

[0002] Diabetes is a metabolic disease characterized by high blood sugar. High blood sugar is caused by defects in insulin secretion or its biological function, or both. Long-term high blood sugar leads to chronic damage and dysfunction of various tissues, especially eyes, kidneys, heart, blood vessels, and nerves.

[0003] Glimepiride is a long-acting antidiabetic drug, a third-generation sulfonylurea. Figure 5 , its mechanism of action is to play a role by binding to the sulfonylurea receptor on the surface of pancreatic β-cells, which is connected to the potassium ion channel sensitive to ATP, prompting the potassium ion channel to close, causing cell membrane depolarization, voltage-dependent calcium channel opening, calcium ion influx to cause insulin release, and inhibit the synthesis of liver glucose. In addition, since the effect of glimepiride on cardiovascular potassium ion channels is weaker than other equivalent drugs such as glibenclamide, gliclazide, glibenclamide and glipizide, it causes few adverse cardiovascular reactions. Although it has outstanding efficacy and is cheap, it is a first-line medication for type 2 diabetes, but due to the easy occurrence of hypoglycemia and weight gain, individual patients will have adverse reactions such as skin allergic reactions, leukopenia, and secondary failures will occur during use. Therefore, it is of great significance to carry out structural optimization, so the application proposes a new compound phenylalanine glimepiride derivative and its preparation method. Summary of the invention

[0004] The purpose of the present invention is to solve the shortcomings of the prior art mentioned in the background technology, and to propose a phenylalanine glimepiride derivative and a preparation method thereof.

[0005] In order to achieve the above object, the present invention adopts the following technical solutions:

[0006] A phenylalanine glimepiride derivative, comprising L-phenylalanine methyl ester and a pharmaceutically acceptable reaction material;

[0007] Prepared by the following method:

[0008] S1, dissolving L-phenylalanine methyl ester in an organic solvent, then adding phenyl chloroformate, then adding a base, reacting at room temperature for 0.5-6 hours, adding 1M dilute hydrochloric acid, extracting, drying the organic phase with anhydrous sodium sulfate, filtering and evaporating to obtain a crude product, and directly proceeding to the next step;

[0009] S2. Dissolve the crude product 4-[2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido)ethyl]-benzenesulfonamide (CAS: 119018-29-0) in an organic solvent, add a base, reflux for 2-12 hours, remove the solvent by distillation under reduced pressure, add ethyl acetate and 1M sodium hydroxide aqueous solution (V / V=1:1), stir and react for 0.5-3 hours, separate the liquids, adjust the pH of the aqueous phase to 2-3 with concentrated hydrochloric acid, stir overnight and filter to obtain a white solid, dry to obtain a phenylalanine glimepiride derivative.

[0010] As a further feature of the method of the present invention, the organic solvent described in S1 and S2 refers to N,N-dimethylformamide, dichloromethane, tetrahydrofuran, ethyl acetate, chloroform, and acetonitrile.

[0011] As a further feature of the method of the present invention, the base in S1 refers to 4-(dimethylamino)pyridine, triethylamine, diisopropylethylamine, pyridine, sodium bicarbonate, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

[0012] As a further feature of the method of the present invention, the base in S2 refers to triethylamine, pyridine, or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

[0013] Compared with the prior art, the present invention has the following beneficial effects:

[0014] The phenylalanine glimepiride derivative of the present invention replaces the chiral six-membered ring in the original structure with phenylalanine, thereby increasing the solubility of the compound in water. The preparation method of the structure has simple reaction conditions, high yield, and is easy to separate and purify. The reagents used are all commonly used reagents. The phenylalanine glimepiride derivative after structural optimization has maintained activity and improved water solubility. The technical method efficiently synthesizes the phenylalanine glimepiride derivative, and the preliminary activity test results are good, which provides the possibility for subsequent further pharmacological research and also provides a new method for structural modification of the compound. At the same time, the method can conveniently realize 100-gram-level preparation in the laboratory and is suitable for large-scale production. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 Schematic diagram of the molecular formula of the compound L-phenylalanine methyl ester;

[0016] Figure 2 It is a schematic diagram of the molecular formula of crude 4-[2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido)ethyl]-benzenesulfonamide (CAS: 119018-29-0);

[0017] Figure 3The accompanying drawings of the abstract are schematic diagrams of the molecular formula of phenylalanine glimepiride derivatives;

[0018] Figure 4 Schematic diagram of the synthetic route of phenylalanine glimepiride derivatives;

[0019] Figure 5 Schematic diagrams of molecular formulas of different glimepiride, glibourea, gliclazide, glibenclamide and glipizide in the prior art; DETAILED DESCRIPTION

[0020] The content of the present invention can be more easily understood by selecting the following detailed description of the preferred implementation method of the present invention and the embodiments included. Unless otherwise specified, all technical and scientific terms used herein have the same meanings as those of ordinary skill in the art to which the present invention belongs. When there is a conflict, the definition in this specification shall prevail.

[0021] As used herein, the term "prepared from" is synonymous with "comprising." As used herein, the terms "comprising," "including," "having," "containing," or any other variation thereof, are intended to cover a non-exclusive inclusion. For example, a composition, process, method, article, or apparatus that comprises the listed elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, process, method, article, or apparatus.

[0022] The conjunction "consisting of excludes any unspecified element, step, or component. If used in a claim, this phrase renders the claim closed-ended so that it does not include materials other than those described, except for conventional impurities associated therewith. When the phrase "consisting of" appears in a clause of the body of a claim rather than immediately following the subject matter, it limits only the elements described in that clause; other elements are not excluded from the claim as a whole.

[0023] When amount, concentration or other value or parameter is expressed as range, preferred range or a series of upper preferred value and lower preferred value limit range, this should be understood as specifically disclosing all ranges formed by any pairing of any range upper limit or preferred value and any range lower limit or preferred value, regardless of whether the range is disclosed separately. For example, when disclosing range "1 to 5", described range should be interpreted as including range "1 to 4", "1 to 3", "1 to 2", "1 to 2 and 4 to 5", "1 to 3 and 5" etc. When numerical range is described in this article, unless otherwise stated, the range is intended to include its end value and all integers and fractions within the range.

[0024] Singular forms include plural references unless the context clearly indicates otherwise. "Optional" or "either" means that the subsequently described event or incident may or may not occur, and that the description includes instances where the event occurs and instances where it does not.

[0025] Approximate terms in the specification and claims are used to modify quantities, indicating that the present invention is not limited to the specific quantity, but also includes acceptable and modified parts close to the quantity without causing changes in the relevant basic functions. Accordingly, the use of "about", "approximately", etc. to modify a numerical value means that the present invention is not limited to the exact numerical value. In some examples, the approximate terms may correspond to the accuracy of the instrument for measuring the numerical value. In the specification and claims of this application, range limitations can be combined and / or interchanged, and if not otherwise stated, these ranges include all subranges contained therein.

[0026] In addition, the indefinite articles "a" and "an" before the elements or components of the present invention have no restrictions on the quantity requirements (i.e. the number of occurrences) of the elements or components. Therefore, "a" or "an" should be interpreted as including one or at least one, and the elements or components in the singular form also include the plural form, unless the number is obviously intended to be in the singular form.

[0027] The technical solutions in the embodiments of the present invention will be clearly and completely described below in combination with the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, rather than all the embodiments.

[0028] Embodiment 1

[0029] Reference Figure 1-4 , a phenylalanine glimepiride derivative, comprising L-phenylalanine methyl ester and a pharmaceutically acceptable reaction material;

[0030] Prepared by the following method:

[0031] S1, dissolving L-phenylalanine methyl ester in an organic solvent, then adding phenyl chloroformate, then adding a base, reacting at room temperature for 0.5-6 hours, adding 1M dilute hydrochloric acid, extracting, drying the organic phase with anhydrous sodium sulfate, filtering and evaporating to obtain a crude product, and directly proceeding to the next step;

[0032] S2. Dissolve the crude product 4-[2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido)ethyl]-benzenesulfonamide (CAS: 119018-29-0) in an organic solvent, add a base, reflux for 2-12 hours, remove the solvent by distillation under reduced pressure, add ethyl acetate and 1M sodium hydroxide aqueous solution (V / V=1:1), stir and react for 0.5-3 hours, separate the liquids, adjust the pH of the aqueous phase to 2-3 with concentrated hydrochloric acid, stir overnight and filter to obtain a white solid, dry to obtain a phenylalanine glimepiride derivative.

[0033] The organic solvents described in S1 and S2 above refer to N,N-dimethylformamide, dichloromethane, tetrahydrofuran, ethyl acetate, chloroform, and acetonitrile;

[0034] The base described in S1 refers to 4-(dimethylamino)pyridine, triethylamine, diisopropylethylamine, pyridine, sodium bicarbonate, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU);

[0035] The base described in S2 refers to triethylamine, pyridine, and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

[0036] Embodiment 2

[0037] Reference Figure 1-4 , Preparation method of phenylalanine glimepiride derivative, dissolve compound (L-phenylalanine methyl ester) (10.33g, 1.5eq) in 70 ml of dichloromethane, then add phenyl chloroformate (5g, 1eq), and then add triethylamine (3eq). React at room temperature for 0.5-6 hours, add 1M dilute hydrochloric acid, extract, dry the organic phase with anhydrous sodium sulfate, filter and evaporate to dryness to obtain a crude product, and directly proceed to the next step;

[0038] The crude product 4-[2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido)ethyl]-benzenesulfonamide (10.1 g, 0.9 eq) was dissolved in acetonitrile, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (1.5 eq) was added, and the reaction was refluxed for 2-12 hours. The acetonitrile was removed by distillation under reduced pressure, ethyl acetate and 1M sodium hydroxide aqueous solution (V / V=1:1) were added, and the reaction was stirred for 0.5-3 hours, and then the liquids were separated. The pH of the aqueous phase was adjusted to 2-3 with concentrated hydrochloric acid, and the mixture was stirred overnight and filtered to obtain a white solid, which was dried to obtain the product (phenylalanine glimepiride derivative) (8.1 g, 52%).

[0039] 1 H NMR (400 MHz, DMSO- d6)δ13.00(brs,1H),10.63(brs,1H),8.40-8.33(m,1H),7.76-7.72(m,2H), 7.47-7.42(m,2H),7.25-7.15(m,3H),7.00-6.95(m,2H),6.58(d,J=7.6Hz, 1H),4.30-4.22(m,1H),4.12(s,2H),3.52-3.43(m,2H),3.01-2.94(m,1H) ,2.92-2.84(m,3H),2.19-2.11(m,2H),1.98(s,3H),0.94(t,J=7.6Hz,3H).

[0040] Embodiment 3

[0041] Reference Figure 1-4 , Preparation method of phenylalanine glimepiride derivative, compound 2 (L-phenylalanine methyl ester) (10.33g, 1.5eq) is dissolved in 70 ml of dichloromethane, then phenyl chloroformate (5g, 1eq) is added, and then sodium bicarbonate (3eq) is added. The mixture is reacted at room temperature for 0.5-6 hours, 1M dilute hydrochloric acid is added, extracted, the organic phase is dried over anhydrous sodium sulfate, filtered and evaporated to obtain a crude product, which is directly carried out to the next step;

[0042] The crude product 4-[2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido)ethyl]-benzenesulfonamide (10.1 g, 0.9 eq) was dissolved in acetonitrile, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (1.5 eq) was added, and the reaction was refluxed for 2-12 hours. The acetonitrile was removed by distillation under reduced pressure, ethyl acetate and 1M sodium hydroxide aqueous solution (V / V=1:1) were added, and the reaction was stirred for 0.5-3 hours, and then the liquids were separated. The pH of the aqueous phase was adjusted to 2-3 with concentrated hydrochloric acid, and the mixture was stirred overnight and filtered to obtain a white solid, which was dried to obtain a phenylalanine glimepiride derivative (6.23 g, 40%).

[0043] The examples referred to herein are merely illustrative and are used to explain some features of the method of the present invention. The appended claims are intended to claim the widest possible range that can be imagined, and the embodiments presented herein are only illustrations of selected implementations according to the combination of all possible embodiments. Therefore, it is the applicant's intention that the appended claims are not limited by the selection of examples that illustrate the features of the present invention. Some numerical ranges used in the claims also include sub-ranges within them, and changes in these ranges should also be interpreted as being covered by the appended claims where possible.

Claims

1. A phenylalanine glimepiride derivative, characterized in that: Containing L-phenylalanine methyl ester and pharmaceutically acceptable reaction materials; Prepared by the following method: S1, dissolving L-phenylalanine methyl ester in an organic solvent, then adding phenyl chloroformate, then adding a base, reacting at room temperature for 0.5-6 hours, adding 1M dilute hydrochloric acid, extracting, drying the organic phase with anhydrous sodium sulfate, filtering and evaporating to obtain a crude product, and directly proceeding to the next step; S2. Dissolve the crude product 4-[2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido)ethyl]-benzenesulfonamide (CAS: 119018-29-0) in an organic solvent, add a base, reflux for 2-12 hours, remove the solvent by distillation under reduced pressure, add ethyl acetate and 1M sodium hydroxide aqueous solution (V / V=1:1), stir and react for 0.5-3 hours, separate the liquids, adjust the pH of the aqueous phase to 2-3 with concentrated hydrochloric acid, stir overnight and filter to obtain a white solid, dry to obtain a phenylalanine glimepiride derivative.

2. The method for preparing the phenylalanine glimepiride derivative according to claim 1, characterized in that: The organic solvents described in S1 and S2 refer to N,N-dimethylformamide, dichloromethane, tetrahydrofuran, ethyl acetate, chloroform, and acetonitrile.

3. The method for preparing the phenylalanine glimepiride derivative according to claim 1, characterized in that: The base described in S1 refers to 4-(dimethylamino)pyridine, triethylamine, diisopropylethylamine, pyridine, sodium bicarbonate, and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

4. The method for preparing the phenylalanine glimepiride derivative according to claim 1, characterized in that: The base described in S2 refers to triethylamine, pyridine, and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

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