Method for preparing metformin hydrochloride

Abstract

The present disclosure provides a method for preparing metformin hydrochloride, which comprises the following steps: preparing dicyandiamide from urea; and preparing metformin hydrochloride from dicyandiamide. The method of the present disclosure effectively improves the reaction yield and is very suitable for large-scale industrial production.

Description

Technical Field

[0001] The present disclosure relates to the technical field of pharmaceutical intermediate synthesis, and in particular to a method for preparing metformin hydrochloride. Background Art

[0002] Metformin hydrochloride is a typical drug for lowering blood sugar, which is particularly suitable for treating patients with type II diabetes. The drug also has the effects of reducing weight and alleviating hyperinsulinemia and protecting cardiovascular system. In addition, metformin hydrochloride can also be used in combination with other hypoglycemic drugs and is effectively used in the treatment of type II diabetes in clinical practice.

[0003] The existing method for preparing metformin hydrochloride has the disadvantages of complex process and low yield, which needs to be solved urgently. Summary of the invention

[0004] In order to solve the above problems, the present invention provides a new method for synthesizing metformin hydrochloride, which has the advantages of simple process and high yield.

[0005] Specifically, the first aspect of the present disclosure provides a method for preparing metformin hydrochloride, comprising the following steps:

[0006] (1) Preparation of dicyandiamide from urea; and

[0007] (2) preparing metformin hydrochloride from the dicyandiamide.

[0008] Preferably, the step (1) comprises:

[0009] In the reactor, 30g urea, 500mL dimethyl sulfoxide and 46g triethylamine were added in sequence. After being fully mixed, the temperature was raised to 65°C. 23g phosphorus oxychloride was gradually added dropwise under stirring. After the addition was completed in 2 hours, the mixture was reacted for another hour. The mixture was then cooled to room temperature and dimethyl sulfoxide was removed by vacuum distillation. Then 100ml saturated aqueous sodium carbonate solution, 100mL ethanol and 200ml ethyl acetate were added in sequence. After standing for phase separation, the organic phase was concentrated and dried in vacuo to obtain dicyandiamide.

[0010] Preferably, the step (2) comprises:

[0011] In the reactor, 20g of dicyandiamide and 100ml of ethanol were added in sequence. After they were completely dissolved, 28g of dimethylamine aqueous solution was added dropwise under ice bath. After the addition was completed for 1h, the reaction system was heated to room temperature and reacted for another 8h. Then, dilute hydrochloric acid was added dropwise until the pH was 2. Then, 150ml of ether was added, and the mixture was allowed to stand for stratification. The organic phase was removed, and the aqueous phase was evaporated to dryness. Then, an isobutyl alcohol / ethanol mixed solvent was added to the reaction product. The temperature was then raised to 50°C until the reaction product was completely dissolved. After an ice bath for 10h, a large amount of crystals were precipitated. After filtration and vacuum drying, metformin hydrochloride was obtained.

[0012] Preferably, the aqueous dimethylamine solution in step (2) is obtained by mixing dimethylamine and deionized water at a weight ratio of 40:100.

[0013] Preferably, the weight ratio of isobutanol to ethanol in step (2) is 1:1 - 1:20.

[0014] Preferably, the weight ratio of isobutanol to ethanol in step (2) is 1:5 - 1:15.

[0015] Preferably, the weight ratio of isobutanol to ethanol in step (2) is 1:9.

[0016] The second aspect of the present disclosure provides metformin hydrochloride prepared by the above method.

[0017] The third aspect of the present disclosure provides dicyandiamide prepared by the above method.

[0018] The above and other features, aspects, and advantages of the present application are more easily understood with reference to the following detailed description. Specific Embodiments

[0019] Unless otherwise defined, all technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In case of conflict, the definitions in this specification shall prevail.

[0020] Unless otherwise stated, all percentages, parts, ratios, etc. are by weight.

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

[0022] When quantities, weight parts, or other numerical values or parameters are given as ranges, preferred ranges, or a series of upper preferred values and lower preferred values, it should be understood that all ranges formed by any pair of a larger range limit or preferred value and any smaller range limit or preferred value are specifically disclosed, regardless of whether the ranges are separately disclosed. For example, when describing a range of "1 to 5", the described range should be understood to include ranges such as "1 to 4", "1 to 3", "1 to 2", "1 to 2 and 4 to 5", "1 to 3 and 5", etc. Unless otherwise stated, where numerical ranges are described herein, the ranges are intended to include the range endpoints and all integers and fractions within the range.

[0023] In addition, the indefinite articles "a" and "an" before the elements or components of the present disclosure are intended to indicate that the number of occurrences (i.e., occurrences) of the elements or components is not limited. Therefore, "a" or "an" should be understood to include one or at least one, unless it is clearly indicated that the number is singular, otherwise the elements or components in the singular form also include the plural case.

[0024] Unless specifically stated, the materials, methods, and examples described herein are illustrative only and not limiting. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are still described herein.

[0025] The present disclosure is described in detail below.

[0026] Embodiment

[0027] Example 1

[0028] A method for preparing metformin hydrochloride, comprising the steps of:

[0029] (1) Preparation of dicyandiamide from urea

[0030] In the reactor, 30g urea, 500mL dimethyl sulfoxide and 46g triethylamine were added in sequence. After being fully mixed, the temperature was raised to 65°C. 23g phosphorus oxychloride was gradually added dropwise under stirring. After the addition was completed in 2 hours, the mixture was reacted for another hour. The mixture was then cooled to room temperature and dimethyl sulfoxide was removed by vacuum distillation. Then 100ml saturated sodium carbonate aqueous solution, 100mL ethanol and 200ml ethyl acetate were added in sequence. After standing for phase separation, the organic phase was concentrated and dried in vacuo to obtain dicyandiamide with a yield of 97.9%.

[0031] (2) Preparation of Metformin Hydrochloride from Dicyandiamide

[0032] In the reactor, 20g of dicyandiamide and 100ml of ethanol were added in sequence. After they were completely dissolved, 28g of dimethylamine aqueous solution (dimethylamine and deionized water were mixed in a weight ratio of 40:100) was added dropwise under an ice bath. After the addition was completed for 1h, the reaction system was heated to room temperature and reacted for another 8h. Then, dilute hydrochloric acid was added dropwise until the pH was 2. Then, 150ml of ether was added, and the mixture was allowed to stand for stratification. The organic phase was removed, and the aqueous phase was evaporated to dryness. An isobutyl alcohol / ethanol mixed solvent (the weight ratio of isobutyl alcohol to ethanol was 1:9) was added to the reaction product. The temperature was then raised to 50°C until the reaction product was completely dissolved. After an ice bath for 10h, a large amount of crystals were precipitated. After filtration and vacuum drying, metformin hydrochloride was obtained with a yield of 98.2%.

[0033] Example 2

[0034] A method for preparing metformin hydrochloride, comprising the steps of:

[0035] (1) Preparation of dicyandiamide from urea

[0036] In a reactor, 30 g of urea, 500 mL of dimethyl sulfoxide and 46 g of triethylamine were added in sequence. After thorough mixing, the temperature was raised to 65 °C. Under stirring, 23 g of phosphorus oxychloride was gradually added dropwise over 2 hours. After the addition was completed, the reaction was continued for 1 hour. Then, after cooling to room temperature, dimethyl sulfoxide was removed by vacuum distillation. Subsequently, 100 ml of saturated sodium carbonate aqueous solution, 100 mL of ethanol and 200 ml of ethyl acetate were added in sequence. After standing for phase separation, the organic phase was concentrated and then dried under vacuum to obtain dicyandiamide with a yield of 97.9%.

[0037] (2) Preparation of metformin hydrochloride from dicyandiamide

[0038] In a reactor, 20 g of dicyandiamide and 100 ml of ethanol were added in sequence. After complete dissolution, 28 g of aqueous dimethylamine solution (prepared by mixing dimethylamine and deionized water at a weight ratio of 40:100) was added dropwise under an ice bath. After the addition was completed in 1 hour, the reaction system was heated to room temperature and reacted for another 8 hours. Then, dilute hydrochloric acid was added dropwise until the pH reached 2. After adding 150 ml of ether, the mixture was allowed to stand for layer separation. The organic phase was removed, and the aqueous phase was evaporated to dryness. Then, an isobutanol / ethanol mixed solvent (weight ratio of isobutanol to ethanol is 1:5) was added to the reaction product. Then, the temperature was raised to 50 °C until the reaction product was completely dissolved. After ice-bathing for 10 hours, a large amount of crystals precipitated. After filtration and vacuum drying, metformin hydrochloride was obtained with a yield of 95.1%.

[0039] Example 3

[0040] A method for preparing metformin hydrochloride, the steps are as follows:

[0041] (1) Preparation of dicyandiamide from urea

[0042] In a reactor, 30 g of urea, 500 mL of dimethyl sulfoxide and 46 g of triethylamine were added in sequence. After thorough mixing, the temperature was raised to 65 °C. Under stirring, 23 g of phosphorus oxychloride was gradually added dropwise over 2 hours. After the addition was completed, the reaction was continued for 1 hour. Then, after cooling to room temperature, dimethyl sulfoxide was removed by vacuum distillation. Subsequently, 100 ml of saturated sodium carbonate aqueous solution, 100 mL of ethanol and 200 ml of ethyl acetate were added in sequence. After standing for phase separation, the organic phase was concentrated and then dried under vacuum to obtain dicyandiamide with a yield of 97.9%.

[0043] (2) Preparation of metformin hydrochloride from dicyandiamide

[0044] In a reactor, 20 g of dicyandiamide and 100 ml of ethanol were added successively. After complete dissolution, 28 g of aqueous dimethylamine solution (prepared by mixing dimethylamine and deionized water in a weight ratio of 40:100) was added dropwise under an ice bath. After the addition was completed in 1 h, the reaction system was raised to room temperature and reacted for another 8 h. Then, dilute hydrochloric acid was added dropwise until the pH reached 2. After that, 150 ml of diethyl ether was added, and the mixture was allowed to stand and separate into layers. The organic phase was removed, and the aqueous phase was evaporated to dryness. Then, an isobutanol / ethanol mixed solvent (weight ratio of isobutanol to ethanol is 1:15) was added to the reaction product. Then, the temperature was raised to 50 °C until the reaction product was completely dissolved. After ice-bathing for 10 h, a large amount of crystals precipitated. After filtration and vacuum drying, metformin hydrochloride was obtained with a yield of 96.0%.

[0045] Example 4

[0046] A method for preparing metformin hydrochloride, the steps of which are as follows:

[0047] (1) Preparation of dicyandiamide from urea

[0048] In a reactor, 30 g of urea, 500 mL of dimethyl sulfoxide and 46 g of triethylamine were added successively. After thorough mixing, the temperature was raised to 65 °C. Under stirring, 23 g of phosphorus oxychloride was gradually added dropwise. After the addition was completed in 2 h, the reaction was continued for 1 h. Then, the temperature was lowered to room temperature, and dimethyl sulfoxide was removed by vacuum distillation. Then, 100 ml of saturated sodium carbonate aqueous solution, 100 mL of ethanol and 200 ml of ethyl acetate were added successively. After standing and separating into phases, the organic phase was concentrated and then vacuum dried to obtain dicyandiamide with a yield of 97.9%.

[0049] (2) Preparation of metformin hydrochloride from dicyandiamide

[0050] In a reactor, 20 g of dicyandiamide and 100 ml of ethanol were added successively. After complete dissolution, 28 g of aqueous dimethylamine solution (prepared by mixing dimethylamine and deionized water in a weight ratio of 40:100) was added dropwise under an ice bath. After the addition was completed in 1 h, the reaction system was raised to room temperature and reacted for another 8 h. Then, dilute hydrochloric acid was added dropwise until the pH reached 2. After that, 150 ml of diethyl ether was added, and the mixture was allowed to stand and separate into layers. The organic phase was removed, and the aqueous phase was evaporated to dryness. Then, an isobutanol / ethanol mixed solvent (weight ratio of isobutanol to ethanol is 1:1) was added to the reaction product. Then, the temperature was raised to 50 °C until the reaction product was completely dissolved. After ice-bathing for 10 h, a large amount of crystals precipitated. After filtration and vacuum drying, metformin hydrochloride was obtained with a yield of 87.8%.

[0051] Example 6

[0052] A method for preparing metformin hydrochloride, the steps of which are as follows:

[0053] (1) Preparation of dicyandiamide from urea

[0054] In a reactor, 30 g of urea, 500 mL of dimethyl sulfoxide, and 46 g of triethylamine were added in sequence. After thorough mixing, the temperature was raised to 65°C. While stirring, 23 g of phosphorus oxychloride was gradually added dropwise over 2 hours. After addition was complete, the reaction was continued for 1 hour. Then, after cooling to room temperature, dimethyl sulfoxide was removed by vacuum distillation. Subsequently, 100 ml of saturated sodium carbonate aqueous solution, 100 mL of ethanol, and 200 ml of ethyl acetate were added in sequence. After standing for phase separation, the organic phase was concentrated and then dried under vacuum to obtain dicyandiamide with a yield of 97.9%.

[0055] (2) Preparation of metformin hydrochloride from dicyandiamide

[0056] In a reactor, 20 g of dicyandiamide and 100 ml of ethanol were added in sequence. After complete dissolution, 28 g of aqueous dimethylamine solution (prepared by mixing dimethylamine and deionized water at a weight ratio of 40:100) was added dropwise under an ice bath. After the addition was completed in 1 hour, the reaction system was warmed to room temperature and the reaction was continued for 8 hours. Then, dilute hydrochloric acid was added dropwise until the pH reached 2. Subsequently, 150 ml of ether was added, and after standing for layer separation, the organic phase was removed. After the aqueous phase was evaporated to dryness, an isobutanol / ethanol mixed solvent (weight ratio of isobutanol to ethanol is 1:20) was added to the reaction product. Then, the temperature was raised to 50°C until the reaction product was completely dissolved. After ice bath for 10 hours, a large amount of crystals precipitated. After filtration and drying under vacuum, metformin hydrochloride was obtained with a yield of 88.1%.

[0057] Comparative Example 1

[0058] A method for preparing metformin hydrochloride, the steps of which are as follows:

[0059] (1) Preparation of dicyandiamide from urea

[0060] In a reactor, 30 g of urea, 500 mL of dimethyl sulfoxide, and 46 g of triethylamine were added in sequence. After thorough mixing, the temperature was raised to 65°C. While stirring, 23 g of phosphorus oxychloride was gradually added dropwise over 2 hours. After addition was complete, the reaction was continued for 1 hour. Then, after cooling to room temperature, dimethyl sulfoxide was removed by vacuum distillation. Subsequently, 100 ml of saturated sodium carbonate aqueous solution, 100 mL of ethanol, and 200 ml of ethyl acetate were added in sequence. After standing for phase separation, the organic phase was concentrated and then dried under vacuum to obtain dicyandiamide with a yield of 97.9%.

[0061] (2) Preparation of metformin hydrochloride from dicyandiamide

[0062] In a reactor, 20 g of dicyandiamide and 100 ml of ethanol were added successively. After complete dissolution, 28 g of aqueous dimethylamine solution (obtained by mixing dimethylamine and deionized water at a weight ratio of 40:100) was added dropwise under an ice bath. After the addition was completed in 1 h, the reaction system was raised to room temperature and reacted for another 8 h. Then, dilute hydrochloric acid was added dropwise until the pH reached 2. After that, 150 ml of diethyl ether was added, and the mixture was allowed to stand and separate into layers. The organic phase was removed, and the aqueous phase was evaporated to dryness. Ethanol was added to the reaction product, and then the temperature was raised to 50 °C until the reaction product was completely dissolved. After ice-bathing for 10 h, a large amount of crystals precipitated. After filtration and vacuum drying, metformin hydrochloride was obtained with a yield of 85.5%.

[0063] Comparative Example 2

[0064] A method for preparing metformin hydrochloride, the steps of which are as follows:

[0065] (1) Preparation of dicyandiamide from urea

[0066] In a reactor, 30 g of urea, 500 mL of dimethyl sulfoxide and 46 g of triethylamine were added successively. After thorough mixing, the temperature was raised to 65 °C, and 23 g of phosphorus oxychloride was gradually added dropwise with stirring. After the addition was completed in 2 h, the reaction was continued for 1 h. Then, the temperature was lowered to room temperature, and dimethyl sulfoxide was removed by vacuum distillation. Then, 100 ml of saturated sodium carbonate aqueous solution, 100 mL of ethanol and 200 ml of ethyl acetate were added successively. After standing and separating into phases, the organic phase was concentrated and then dried under vacuum to obtain dicyandiamide with a yield of 97.9%.

[0067] (2) Preparation of metformin hydrochloride from dicyandiamide

[0068] In a reactor, 20 g of dicyandiamide and 100 ml of ethanol were added successively. After complete dissolution, 28 g of aqueous dimethylamine solution (obtained by mixing dimethylamine and deionized water at a weight ratio of 40:100) was added dropwise under an ice bath. After the addition was completed in 1 h, the reaction system was raised to room temperature and reacted for another 8 h. Then, dilute hydrochloric acid was added dropwise until the pH reached 2. After that, 150 ml of diethyl ether was added, and the mixture was allowed to stand and separate into layers. The organic phase was removed, and the aqueous phase was evaporated to dryness. Isobutanol was added to the reaction product, and then the temperature was raised to 50 °C until the reaction product was completely dissolved. After ice-bathing for 10 h, a large amount of crystals precipitated. After filtration and vacuum drying, metformin hydrochloride was obtained with a yield of 71.9%.

[0069] Although the specific embodiments of the present disclosure have been described above, those skilled in the art should understand that these are only examples. The protection scope of the present disclosure is defined by the appended claims. Without departing from the principles and essence of the present disclosure, those skilled in the art can make various changes or modifications to these embodiments, but these changes and modifications all fall within the protection scope of the present disclosure.

Claims

1. A method for preparing metformin hydrochloride, It is characterized in that It includes the following steps: (1) Preparation of dicyandiamide from urea; and (2) preparing metformin hydrochloride from the dicyandiamide; The step (1) comprises: In a reactor, 30 g of urea, 500 mL of dimethyl sulfoxide and 46 g of triethylamine were added in sequence, and after being fully mixed, the temperature was raised to 65° C., and 23 g of phosphorus oxychloride was gradually added dropwise under stirring. After the addition was completed in 2 hours, the mixture was reacted for another hour, and then the temperature was lowered to room temperature, and the dimethyl sulfoxide was removed by distillation under reduced pressure. Then, 100 ml of saturated sodium carbonate aqueous solution, 100 ml of ethanol and 200 ml of ethyl acetate were added in sequence, and after standing for phase separation, the organic phase was concentrated and vacuum dried to obtain dicyandiamide; The step (2) comprises: In a reactor, 20 g of dicyandiamide and 100 ml of ethanol are added in sequence. After they are completely dissolved, 28 g of dimethylamine aqueous solution is added dropwise under an ice bath. After the addition is completed for 1 hour, the reaction system is heated to room temperature and reacted for another 8 hours. Then, dilute hydrochloric acid is added dropwise until the pH is 2. Then, 150 ml of ether is added, and the mixture is allowed to stand for stratification. The organic phase is removed, and the aqueous phase is evaporated to dryness. An isobutyl alcohol / ethanol mixed solvent is added to the reaction product, and then the temperature is raised to 50° C. until the reaction product is completely dissolved. After an ice bath for 10 hours, a large amount of crystals are precipitated, which are filtered and vacuum dried to obtain metformin hydrochloride; The dimethylamine aqueous solution in step (2) is obtained by mixing dimethylamine and deionized water in a weight ratio of 40:100; In the step (2), the weight ratio of isobutanol to ethanol is 1:1-1:

20.

2. The method according to claim 1, It is characterized in that In the step (2), the weight ratio of isobutanol to ethanol is 1:5-1:

15.

3. The method according to claim 1, It is characterized in that The weight ratio of isobutanol to ethanol in step (2) is 1:9.