WO2022241978A1 - 盐酸二甲双胍的合成方法及应用 - Google Patents
盐酸二甲双胍的合成方法及应用 Download PDFInfo
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- WO2022241978A1 WO2022241978A1 PCT/CN2021/118251 CN2021118251W WO2022241978A1 WO 2022241978 A1 WO2022241978 A1 WO 2022241978A1 CN 2021118251 W CN2021118251 W CN 2021118251W WO 2022241978 A1 WO2022241978 A1 WO 2022241978A1
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- metformin hydrochloride
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- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin hydrochloride Natural products CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 title claims abstract description 78
- 229960004329 metformin hydrochloride Drugs 0.000 title claims abstract description 76
- OETHQSJEHLVLGH-UHFFFAOYSA-N metformin hydrochloride Chemical compound Cl.CN(C)C(=N)N=C(N)N OETHQSJEHLVLGH-UHFFFAOYSA-N 0.000 title claims abstract description 76
- 238000000034 method Methods 0.000 title claims abstract description 24
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 53
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 15
- QGBSISYHAICWAH-UHFFFAOYSA-N dicyandiamide Chemical compound NC(N)=NC#N QGBSISYHAICWAH-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000007939 sustained release tablet Substances 0.000 claims abstract description 14
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims abstract description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000011734 sodium Substances 0.000 claims abstract description 8
- 229910052708 sodium Inorganic materials 0.000 claims abstract description 8
- -1 sodium alkoxide Chemical class 0.000 claims abstract description 8
- 238000006482 condensation reaction Methods 0.000 claims abstract description 5
- 238000001308 synthesis method Methods 0.000 claims description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 238000010189 synthetic method Methods 0.000 claims description 8
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical group [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 5
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- 238000010979 pH adjustment Methods 0.000 claims 1
- 238000002156 mixing Methods 0.000 abstract description 16
- 230000015572 biosynthetic process Effects 0.000 abstract description 9
- 238000003786 synthesis reaction Methods 0.000 abstract description 9
- 239000003814 drug Substances 0.000 abstract description 7
- 229940079593 drug Drugs 0.000 abstract description 6
- 238000005265 energy consumption Methods 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 238000000746 purification Methods 0.000 abstract description 5
- 230000002378 acidificating effect Effects 0.000 abstract description 2
- 239000002904 solvent Substances 0.000 description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- 239000000463 material Substances 0.000 description 11
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 10
- 239000000243 solution Substances 0.000 description 8
- 238000009835 boiling Methods 0.000 description 7
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- 238000003756 stirring Methods 0.000 description 6
- 239000003826 tablet Substances 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- XHFGWHUWQXTGAT-UHFFFAOYSA-N dimethylamine hydrochloride Natural products CNC(C)C XHFGWHUWQXTGAT-UHFFFAOYSA-N 0.000 description 5
- IQDGSYLLQPDQDV-UHFFFAOYSA-N dimethylazanium;chloride Chemical compound Cl.CNC IQDGSYLLQPDQDV-UHFFFAOYSA-N 0.000 description 5
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 5
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 5
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 5
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 5
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- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 239000003472 antidiabetic agent Substances 0.000 description 3
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- 238000013112 stability test Methods 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 238000007259 addition reaction Methods 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 229960000935 dehydrated alcohol Drugs 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
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- 238000003912 environmental pollution Methods 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- 238000004255 ion exchange chromatography Methods 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 229960003105 metformin Drugs 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
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- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 2
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- 206010060378 Hyperinsulinaemia Diseases 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 238000000889 atomisation Methods 0.000 description 1
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- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
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- 235000005911 diet Nutrition 0.000 description 1
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Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C279/20—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylguanidines
- C07C279/24—Y being a hetero atom
- C07C279/26—X and Y being nitrogen atoms, i.e. biguanides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C277/00—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C277/08—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups of substituted guanidines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
Definitions
- the invention belongs to the field of drug synthesis, and relates to a synthesis method and application of hypoglycemic drugs, in particular to a synthesis method and application of metformin hydrochloride.
- Metformin Hydrochloride is a white crystalline powder, odorless.
- the molecular formula is C 4 H 12 ClN 5 , the molecular weight is 165.62, and its structural formula is:
- Metformin hydrochloride is a hypoglycemic drug for treating type II diabetic patients with the characteristics of obesity, unsatisfactory diet control and ineffective physical exercise.
- the drug can not only lower blood sugar, but also reduce weight, and has the effect of reducing hyperinsulinemia.
- it has also been proven to have a clear protective cardiovascular effect, and can be used as the basic drug for the whole course of treatment of patients with type II diabetes.
- a first-line drug for the treatment of type II diabetes it can form a compound preparation with other oral hypoglycemic drugs, and has a good clinical effect. Therefore, the drug is currently the core drug for controlling diabetes in the world.
- the melting method is also called the dry method. It is a method of adding reaction after heating and melting the reactants in a solvent-free system. Since the reaction does not require a solvent, no toxic and harmful reagents are introduced, and there is no need to consider solvent recovery, liquid Waste treatment and other issues can better control the "three wastes". However, because the melting method has no solvent, the fluidity during the reaction is poor, the reactants are heated unevenly, and the reaction is insufficient, resulting in many side reactions, which have a great impact on the purity and yield of the product. At the same time, because no solvent is used, the reaction process lacks heat. Control, the system is not uniform after the reaction, and the operation is complicated.
- the organic solvent is used in the reaction process of the solvent method. It does not participate in the reaction as an intermediate medium. It can dissolve dicyandiamide and dimethylamine hydrochloride very well, promote the reaction to proceed in a homogeneous phase, and the heat is stable. The reaction is fully carried out and the process control is convenient. ; but the reaction needs to be heated to 130-150 ° C, and the reagents used are mostly high-boiling solvents such as cyclohexanol and benzene. In the process of refining the product, it is not only unfriendly to the environment, but also increases the impact on the product. The difficulty of refining, the solvent is easy to remain in the product and affects the purity of the product, while increasing the amount of alcohol reagents in the refining process.
- metformin hydrochloride in the prior art has defects such as that the purity cannot meet the requirements, the purification difficulty is large, the energy consumption is high, and the environmental pollution is large.
- the most important thing is that the product purity and impurity content after the addition reaction of dicyandiamide and dimethylamine hydrochloride are difficult to meet Requirements, so seeking a kind of refining method of metformin hydrochloride is imminent.
- the present invention aims to provide a synthetic method of metformin hydrochloride, so as to reduce the energy consumption of the reaction, reduce the difficulty of purification, and reduce environmental pollution.
- a method for synthesizing metformin hydrochloride is to dissolve dicyandiamide and dimethylamine in lower alcohols, add sodium alkoxide, mix evenly, and gradually increase the temperature to carry out condensation reaction. After the reaction, add hydrochloric acid to adjust the pH to acidic Afterwards, promptly obtain described metformin hydrochloride, its reaction formula is:
- the lower alcohol is methanol, ethanol, propanol or ethylene glycol
- the sodium alkoxide is sodium methoxide or sodium ethoxide
- the gradual increase in temperature is to increase the temperature by 5°C every 10 minutes, the maximum reaction temperature is raised to 80°C, and the lowest temperature of the reaction temperature is 40°C;
- the reaction temperature of the condensation reaction is 40-80°C, and the reaction time is 2-5 hours;
- the molar ratio of dicyandiamide to dimethylamine is 1:1 to 1.3; the molar ratio of sodium alkoxide to dicyandiamide is 2 to 2.8:1;
- the present invention also provides an application of the synthesis method of metformin hydrochloride, the synthesis method is used to synthesize metformin hydrochloride; the synthesized metformin hydrochloride is used to prepare metformin hydrochloride sustained-release tablets.
- the synthetic method of metformin hydrochloride provided by the present invention controls reaction rate by gradually increasing temperature, reduces temperature of reaction simultaneously, has reduced the energy consumption in the reaction process, has indirectly reduced production cost;
- the present invention adopts the mode of gradually warming up to carry out gradually heating and promoting reaction to carry out, because adding sodium alkoxide to directly heat up may cause the reaction to be too violent, thereby causing accidents such as material spraying, reaction vessel rupture, so adopt gradually warming up to control reaction rate;
- the synthetic method of metformin hydrochloride provided by the present invention adopts a low-boiling point solvent, which can be recovered by concentrating under reduced pressure, and the recovered solvent can be reused to avoid directly discarding and polluting the environment.
- the synthesis method of metformin hydrochloride provided by the present invention reduces the energy consumption in the reaction process, reduces the production cost, and reduces the difficulty of product purification.
- the invention is applicable to the synthesis of metformin hydrochloride, and the synthesized metformin hydrochloride is used for preparing metformin hydrochloride sustained-release tablets.
- Figure 1 is an ion chromatogram of metformin hydrochloride A1 synthesized in Example 1 of the present invention.
- Embodiment 1 A kind of synthetic method of metformin hydrochloride A1
- This example provides a synthesis method of metformin hydrochloride A1, the synthesis method is to weigh 16.8g of dicyandiamide and add it to 50ml of methanol for dissolution, after stirring evenly, add 9.1g of dimethylamine, after stirring and dissolving, add 27g of sodium methoxide , raise the temperature by 5°C every ten minutes until the reaction temperature is 30°C, keep warm and stir for 5h, take a small amount of reaction solution after 5h, and monitor the reaction process by ion chromatography after dilution, the ion peak of dicyandiamide disappears, and a new peak appears, and the molecular weight is 130.17 (M + ), this peak is the ion peak of metformin, which is the end point of the reaction.
- Table 1 Specific process parameter table of metformin hydrochloride A2 ⁇ A4
- the synthesis method of metformin hydrochloride provided in this comparative example is basically the same as that in Example 1, the difference being that the reaction temperature is different, and the specific reaction temperature is shown in Table 2.
- the synthesis method of metformin hydrochloride provided in this comparative example is basically the same as in Example 1, the difference is that the synthesis is carried out by directly raising the temperature (that is, rapidly raising the temperature or raising the temperature at a rate of 1° C./min or higher) to 70° C. During the heating process, A large number of bubbles are generated in the reaction solution, and part of the reaction solution overflows from the mouth of the reaction container. At the same time, the thermometer shows that the temperature of the reaction solution rises rapidly. After adding an explosion-proof plate, the reaction is closed after 2 hours of reaction. After the reaction solution cools down and no longer bubbling violently, Sampling was sent for inspection, and in the resulting spectrum, no metformin hydrochloride was generated.
- Metformin hydrochloride and sodium carboxymethylcellulose were crushed through 80-mesh sieve before feeding into production; hydroxypropyl methylcellulose K100M, microcrystalline cellulose, and hydroxypropyl methylcellulose E5 were passed through 60-mesh sieve, and the remaining materials Weigh directly for use.
- Granulation set the fan frequency to 35Hz, the air inlet temperature to 80.0°C, set the atomization pressure to 0.35MPa in the inner layer and 0.30MPa in the outer layer (or the inner layer is 0.05MPa larger than the outer layer, but the outer layer is not less than 0.2MPa), set the supply
- the liquid speed is 300r/min.
- the temperature of the material reaches 45°C ⁇ 5°C, it starts to spray water and granulate, and it increases by 25r every 5min.
- the liquid supply frequency reaches 450r/min, until the end of water spraying, when the temperature of the material reaches 42.0 ⁇ 2°C, drop it into the pot to observe the granulation of the material.
- the total amount of water sprayed during granulation is 85kg.
- the second water spray do not turn on the hot air, set the fan frequency to 40Hz, and the liquid supply frequency to 500r/min to spray water to wet the material.
- the frequency of the fan determines the drying speed, and the frequency of the liquid supply determines the spraying speed.
- the total amount of water sprayed during the second water spray is 1/4 to 1/2 of the water sprayed during mixing and granulation.
- Grain sizing Add the prescribed amount of silica into the material compartment and use a lifting and turning granulator to sizing the granulator.
- the sieve of 1.5mm is installed on the granulator, and the silo of the boiling dryer is pushed into the dry granulator.
- the 6 connecting screws connecting the barrel cover are tightened and then sealed; after pushing away the silo trolley, operate the hoist to turn the barrel 180° and raise it to an appropriate height.
- Push the 1000L mixing tank make the outlet of the mixing tank align with the inlet of the dry granulator, align the outlet of the dry granulator with the mouth of the mixing tank and fix it with a hose, start the granulator, and the granulation speed Set to 10Hz, open the discharge knob of the material tank cover to carry out granulation, after the granule discharge is completed, close the discharge knob of the material tank cover to stop the granulator.
- the tablet weight should be determined, and a 19mm*9mm metformin hydrochloride sustained-release tablet special-shaped punch is installed for tablet compression.
- the tablet hardness is controlled at 170N-200N, and the friability must not exceed 0.8%.
- metformin hydrochloride sustained-release tablet According to the preparation method of the metformin hydrochloride sustained-release tablet provided in the application example, the metformin hydrochloride synthesized in comparative examples 1 ⁇ 2 is made metformin hydrochloride sustained-release tablet D1, D2; company) as Metformin Hydrochloride Sustained Release Tablets D3
- Test method refer to the 2015 edition of "Chinese Pharmacopoeia” Stability Test Investigation
- metformin hydrochloride sustained-release tablets prepared by the synthetic metformin hydrochloride provided by the synthetic method provided by the present invention have a smaller impurity increase of only 0.16%, which is better than metformin hydrochloride sustained-release tablets D1 after being placed for 24 months , D2, similar to the stability of commercially available metformin hydrochloride sustained-release tablet D3.
Abstract
本发明属于药物合成领域,公开了一种盐酸二甲双胍的合成方法及应用,所述合成方法是取双氰胺和二甲胺溶于低级醇后,加入醇钠,混合均匀后逐渐提升温度进行缩合反应,反应结束后,加入盐酸调节pH至酸性,即得所述的盐酸二甲双胍。本发明所提供的盐酸二甲双胍的合成方法,减少了反应过程中的能量消耗,降低了生产成本,降低了产物纯化难度。本发明适用于盐酸二甲双胍的合成,所合成的盐酸二甲双胍用于制备盐酸二甲双胍缓释片。
Description
本发明属于药物合成领域,涉及一种降糖类药物的合成方法及应用,具体地说是一种盐酸二甲双胍的合成方法及应用。
盐酸二甲双胍(Metformin Hydrochloride)是一种白色结晶性粉末,无臭。分子式为C
4H
12ClN
5,分子量为165.62,其结构式为:
盐酸二甲双胍是一种治疗具有肥胖、单纯饮食控制不满意及体育锻炼无效等特点的II型糖尿病患者的降血糖药物。该药物不但可以降低血糖,还能减轻体重,有减轻高胰岛素血症效果。同时还被证明具有明确的保护心血管作用,可以作为II型糖尿病患者的全程治疗的基础药物。此外,作为治疗II型糖尿病的一线药物,可以与其他口服降糖药形成复方制剂,并在临床上有良好的效果。因此,该药目前是全球控制糖尿病的核心药物。
目前市场上通过双氰胺和盐酸二甲胺在130~150℃下进行加成反应,其中主要反应方法有两种,即熔融法和溶媒法。
熔融法也叫干法,是在无溶剂的体系中,对反应物进行加热熔融之后进行加成反应的方法,由于反应不需要溶剂,即不引入有毒有害试剂,也不需要考虑溶剂回收、液废处理等问题,能较好的控制“三废”。但是,由于熔融法没有溶剂,反应时流动性差,反应物受热不均匀,反应不充分,导致副反应多,对产品的纯度和收率影响很大,同时,由于不使用溶剂,反应过程缺乏热量控制,反应结束后体系不均匀,操作 复杂。
溶媒法的反应过程中使用有机溶剂,作为中间介质不参与反应,能很好的溶解双氰胺和盐酸二甲胺,促使反应均相进行,并且热量稳定,反应进行的很充分,过程控制方便;但是反应的发生需要加热到130~150℃,所用试剂多为环己醇,苯类等高沸点溶剂,在对产物进行精制处理的过程中,不仅对环境不友好,而且还会增加对产物的精制难度,溶剂易残留于产物中影响产物纯度,同时增加精制过程中的醇类试剂的用量。
现有技术生产盐酸二甲双胍存在纯度无法达到要求、纯化难度大、能耗高、环境污染大等缺陷,最主要的是双氰胺和盐酸二甲胺加成反应后的产品纯度和杂质含量难以符合要求,故寻求一种好的盐酸二甲双胍的精制方法迫在眉睫。
发明内容
为解决现有技术中存在的以上不足,本发明旨在提供一种盐酸二甲双胍的合成方法,以达到降低进行反应的能耗,降低纯化难度,减少对环境污染的目的。
为实现上述目的,本发明所采用的技术方案如下:
一种盐酸二甲双胍的合成方法,其合成方法是取双氰胺和二甲胺溶于低级醇后,加入醇钠,混合均匀后逐渐提升温度进行缩合反应,反应结束后,加入盐酸调节pH至酸性后,即得所述的盐酸二甲双胍,其反应式为:
作为本发明的限定,所述低级醇为甲醇、乙醇、丙醇或乙二醇;
作为本发明的第二种限定,所述醇钠为甲醇钠或乙醇钠;
作为本发明的第三种限定,所述逐渐提升温度为每间隔10min提升5℃,反应温度最高提升至80℃,反应温度的最低温度为40℃;
作为本发明的第四种限定,所述缩合反应的反应温度为40~80℃、反应时间为2~5h;
作为本发明的第五种限定,所述双氰胺与二甲胺的摩尔比为1:1~1.3;所述醇钠与双氰胺的摩尔比为2~2.8:1;
本发明还提供盐酸二甲双胍的合成方法的一种应用,所述合成方法用于合成盐酸二甲双胍;所合成的盐酸二甲双胍用于制备盐酸二甲双胍缓释片。
由于采用了上述的技术方案,本发明与现有技术相比,所取得的有益效果是:
(1)本发明所提供的盐酸二甲双胍的合成方法,通过逐渐升温控制反应速率,同时降低了反应温度,减少了反应过程中的能量消耗,间接降低了生产成本;
(2)本发明所提供的盐酸二甲双胍的合成方法,由于所需的反应温度较低,所以所需溶剂均采用低沸点溶剂,降低了盐酸二甲双胍的纯化难度,低沸点溶剂的使用,促使在精制盐酸二甲双胍的过程中,溶剂可以被干燥分离,降低了溶剂的残留;
(3)本发明采用逐渐升温的方式进行逐渐加热促进反应进行,由于加入醇钠直接升温可能会造成反应过于剧烈,从而造成喷料,反应容器破裂等事故,所以采用逐渐升温来控制反应速率;
(4)本发明所提供的盐酸二甲双胍的合成方法,采用低沸点溶剂,可以通过减压浓缩的方式进行回收,所回收的溶剂可以二次利用,避免直接弃用对环境造成污染。
综上所述,本发明所提供的盐酸二甲双胍的合成方法,减少了反应过程中的能量消耗,降低了生产成本,降低了产物纯化难度。
本发明适用于盐酸二甲双胍的合成,所合成的盐酸二甲双胍用于制备盐酸二甲双胍缓释片。
下面结合附图及具体实施例对本发明作更进一步详细说明。
图1为本发明实施例1中所合成的盐酸二甲双胍A1的离子色谱图。
以下结合附图对本发明的优选实施例进行说明。应当理解,此处所描述的优选实施例仅用于说明和理解本发明,并不用于限定本发明。
实施例1 一种盐酸二甲双胍A1的合成方法
本实施例提供了一种盐酸二甲双胍A1的合成方法,其合成方法是称取16.8g双氰胺加入至50ml甲醇溶解,搅拌均匀后,加入9.1g二甲胺,搅拌溶解后,加入27g甲醇钠,每十分钟升温5℃至反应温度为30℃,保温并搅拌5h,5h后取少量反应液,稀释后利用离子色谱监测反应进程,双氰胺的离子峰消失,出现新峰,且分子量为130.17(M
+),该峰即为二甲双胍的离子峰,即为反应终点,反应结束后,浓缩甲醇至干,剩余物料降温至室温后,加入50ml纯化水,滴加15ml浓度为38%的盐酸,调节pH至3,混合搅拌后,再加入200ml乙酸乙酯,混合搅拌20min后,静置分层,有机相浓缩回收,无水硫酸钠干燥,可用于下一次合成;所得水相,减压蒸馏至剩余溶液体积为原有水相体积的五分之一,并将剩余溶液的温度降至室温,加入180ml浓度为80%的乙醇,混合均匀后,停止搅拌,放入冷柜,低温析晶,并在冰水浴下过滤,将滤饼再次溶入20ml纯化水,加入100g活性炭,搅拌10min脱色,过滤后用20ml纯化水清洗滤饼,再次加入120ml浓度为80%的乙醇,混合均匀后,低温析晶7h,过滤,滤饼干燥,即得31.7g盐酸二甲双胍A1,收率为96.3%。其反应式为:
取少量干燥好的盐酸二甲双胍A1,通过乙腈溶解稀释,利用离子色谱检测,检测盐酸二甲双胍A1,其纯度为99.1%,所得离子色谱图如图1所示。
实施例2~4 盐酸二甲双胍A2~A4的合成方法
实施例2~4提供的盐酸二甲双胍A2~A4的合成方法与实施例1基本相同,区别仅在于部分工艺参数不同,具体工艺参数见表1。
表1:盐酸二甲双胍A2~A4的具体工艺参数表
其它参数均与实施例1相同。
对比例1 熔融法合成盐酸二甲双胍
称取16.8g双氰胺和16.2g盐酸二甲胺放入反应容器中,加热至210℃,反应2h后,取样送检,得到的检测结果中出现与实施例1中盐酸二甲双胍的吸收峰相同位置且相同分子量的吸收峰,但检测图谱中含有较多杂质峰,经后处理得盐酸二甲双胍的 收率为82.1%,纯度为95.4%。
对比例2 溶媒法合成盐酸二甲双胍
称取16.8g双氰胺和16.2g盐酸二甲胺放入反应容器中,加入甲苯溶解后,加热至150℃,反应2h后,取样送检,得到的检测结果中出现与实施例1中盐酸二甲双胍的离子峰相同位置且相同分子量的离子峰,但测得纯度不高,稀释后注入液相色谱仪中检测,所得谱图中甲苯的溶剂峰明显,经冷却,浓缩,加入无水乙醇结晶,过滤,取样送检,所得结果中甲苯的溶剂峰依旧明显,反复用无水乙醇洗涤5次,每次洗涤用无水乙醇200ml,检测结果中的甲苯溶剂峰消失,所得盐酸二甲双胍的纯度为98.3%,收率为91.3%。
对比例3 盐酸二甲双胍的合成条件对比①
本对比例中提供的盐酸二甲双胍的合成方法与实施例1基本相同,区别在于反应温度不同,具体反应温度见表2。
表2:盐酸二甲双胍的合成反应温度表
对比例4 盐酸二甲双胍的合成条件对比②
本对比例中提供的盐酸二甲双胍的合成方法与实施例1基本相同,区别在于采用直接升温(即快速升温或以1℃/min或更高速度升温)至70℃进行合成,在加热过程中,反应液中产生大量气泡,有部分反应液从反应容器口处溢出,同时温度计显示反应液升温迅速,加设防爆板后,反应2h后关闭反应,待反应液降温并不再剧烈鼓 泡后,取样送检,所得图谱中,没有盐酸二甲双胍生成。
应用例 盐酸二甲双胍缓释片的制备
随机选取实施例1~4所合成的盐酸二甲双胍A1~A4中的一种,制备盐酸二甲双胍缓释片,具体制备方法如下:
1)粉碎过筛
在投料生产前对盐酸二甲双胍、羧甲基纤维素钠分别粉碎过80目筛;羟丙基甲基纤维素K100M、微晶纤维素、羟丙基甲基纤维素E5过60目筛,其余物料直接称量备用。
2)制粒
混合:将过筛后的盐酸二甲双胍、羧甲纤维素钠加入到沸腾干燥制粒机内,风机设置35Hz,不开加热,混合10min。
制粒:设置风机频率至35Hz、进风温度80.0℃、设置雾化压力内层0.35MPa、外层0.30MPa(或内层较外层大0.05MPa,但是外层不小于0.2MPa),设置供液速度300r/min,待物料温度达到45℃±5℃时开始喷水制粒,每隔5min提升25r。当供液频率达到450r/min时,直至喷水结束,物料温度达到42.0±2℃时落锅观察物料成粒情况。此处制粒时的喷水总量为85kg。
第二次喷水:不开热风,设置风机频率40Hz,供液频率500r/min喷水打湿物料。风机频率决定干燥速度,供液频率决定喷水速度。第二次喷水时的喷水总量为混合制粒时喷水量的1/4~1/2。
混合:将处方量1/3的羟丙基甲基纤维素K100M抽加入到沸腾干燥制粒机中,混合干燥5~10min。
整粒:将处方量二氧化硅加入物料舱中使用提升翻转整粒机进行整粒,整粒机安装1.5mm的筛网,将沸腾干燥机的料仓推入干法整粒机下,将联接料桶盖的6个联接螺钉拧紧后密封;将料仓小车推走后,操作提升机将料桶翻转180°并上升至适当高 度。推进1000L混合罐,使混合桶出料口对准干法整粒机的入料口,干法整粒机的出料口对准混合罐口并用软管固定,启动整粒机,整粒转速设置10Hz,打开料桶盖出料旋钮,进行整粒,整粒出料结束后,关闭料桶盖出料旋钮,停止整粒机。
3)总混
打开混合机料斗盖,将剩余处方量的羟丙基甲基纤维素K100M、羟丙基甲基纤维素E5、微晶纤维素、硬脂酸镁加入物料舱中,投入整粒完成的颗粒,盖上并箍紧料斗盖,设定混合时间为25min,混合转速为10r/min,按下混合位按钮开始混合。混合完毕后,在放料口取样量送检中间体颗粒。
4)压片
依据中间体颗粒含量制定应压片重,安装19mm*9mm盐酸二甲双胍缓释片专用异形冲进行压片,片剂硬度控制在170N~200N,脆碎度不得超过0.8%。
5)泡罩包装
选择8片/板或10片/板模具进行包装。领取中间产品、PVC与铝箔,安装好成形模具,热封模具,印字模具,冲栽模具,设置全自动高速泡罩包装机空气压力0.6MPa~0.8MPa,上、下成形模温度120~140℃、热封温度200℃~240℃、20~45Hz冲栽速度,进行包装,即得盐酸二甲双胍缓释片M。
实验例 盐酸二甲双胍缓释片的稳定性试验
根据应用例中提供的盐酸二甲双胍缓释片的制备方法,将对比例1~2中所合成的盐酸二甲双胍制成盐酸二甲双胍缓释片D1、D2;采购盐酸二甲双胍缓释片(青岛黄海制药有限责任公司)作为盐酸二甲双胍缓释片D3
试验方法:参照2015年版《中国药典》第二部稳定性试验考察
试验条件:
长期试验温度:25±2℃;长期试验湿度:RH60±10%
长期试验考察时间:0、3、6、9、12、18、24月
试验结果如表3所示。
盐酸二甲双胍缓释片的稳定性试验结果表
结果表明,利用本发明所提供的合成方法所合成的盐酸二甲双胍所制备的盐酸二甲双胍缓释片在放置24个月,其杂质增量较小,仅为0.16%,优于盐酸二甲双胍缓释片D1、D2,与市售盐酸二甲双胍缓释片D3的稳定性相近。
需要说明的是,以上所述仅为本发明的优选实施例而已,并不用于限制本发明,尽管参照上述实施例对本发明进行了详细的说明,对于本领域技术人员来说,其依然可以对上述各实施例所记载的技术方案进行修改,或者对其中部分技术特征进行等同替换。凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (6)
- 根据权利要求1所述的盐酸二甲双胍的合成方法,其特征在于:所述逐渐提升温度为每间隔10min提升5℃,反应温度最高提升至80℃,反应温度的最低温度为20℃。
- 根据权利要求2所述的盐酸二甲双胍的合成方法,其特征在于:所述低级醇为甲醇、乙醇、丙醇或乙二醇;所述醇钠为甲醇钠或乙醇钠。
- 根据权利要求1或3所述的盐酸二甲双胍的合成方法,其特征在于:所述缩合反应的反应温度为40~80℃、反应时间为2~5h。
- 根据权利要求1~3中任意一项所述的盐酸二甲双胍的合成方法,其特征在于:所述双氰胺与二甲胺的摩尔比为1:1~1.3;所述醇钠与双氰胺的摩尔比为2~2.8:1;所述调节pH是利用盐酸调节pH值至1~3。
- 根据权利要求1~5中任意一项所述的盐酸二甲双胍的合成方法的一种应用,其特征在于:所述合成方法用于合成盐酸二甲双胍;所合成的盐酸二甲双胍用于制备盐酸二甲双胍缓释片。
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Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2322860B1 (zh) * | 1975-09-05 | 1979-04-27 | Aron Sa | |
CN101450919A (zh) * | 2007-11-30 | 2009-06-10 | 山东方兴科技开发有限公司 | 盐酸二甲双胍精制方法 |
CN105968032A (zh) * | 2016-05-12 | 2016-09-28 | 宁夏思科达生物科技有限公司 | 盐酸二甲双胍的合成方法 |
CN110256299A (zh) * | 2019-07-25 | 2019-09-20 | 凯莱英生命科学技术(天津)有限公司 | 盐酸二甲双胍的制备方法 |
CN112028795A (zh) * | 2020-09-17 | 2020-12-04 | 重庆医药高等专科学校 | 一种盐酸二甲双胍的合成方法 |
CN113248409A (zh) * | 2021-05-21 | 2021-08-13 | 海南海力制药有限公司 | 盐酸二甲双胍的合成方法及应用 |
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101450918B (zh) * | 2007-11-30 | 2011-08-10 | 山东方兴科技开发有限公司 | 盐酸二甲双胍纯化方法 |
CN101450920B (zh) * | 2007-11-30 | 2011-08-10 | 山东方兴科技开发有限公司 | 盐酸二甲双胍大颗粒结晶生产方法 |
CN102516130A (zh) * | 2011-11-26 | 2012-06-27 | 赤峰万泽制药有限责任公司 | 一种盐酸二甲双胍的制备方法 |
CN103435518B (zh) * | 2013-08-26 | 2015-02-18 | 青岛黄海制药有限责任公司 | 一种盐酸二甲双胍的制备方法 |
CN106278953B (zh) * | 2015-04-24 | 2017-09-29 | 泰山医学院 | 一种提高盐酸二甲双胍纯度的生产方法 |
CN105481726A (zh) * | 2015-12-17 | 2016-04-13 | 石家庄市普力制药有限公司 | 一种盐酸二甲双胍的制备方法 |
CN110194727A (zh) * | 2018-12-05 | 2019-09-03 | 武汉武药制药有限公司 | 一种盐酸二甲双胍的精制方法 |
-
2021
- 2021-05-21 CN CN202110561018.9A patent/CN113248409B/zh active Active
- 2021-09-14 US US17/598,521 patent/US20230234919A1/en active Pending
- 2021-09-14 WO PCT/CN2021/118251 patent/WO2022241978A1/zh unknown
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2322860B1 (zh) * | 1975-09-05 | 1979-04-27 | Aron Sa | |
CN101450919A (zh) * | 2007-11-30 | 2009-06-10 | 山东方兴科技开发有限公司 | 盐酸二甲双胍精制方法 |
CN105968032A (zh) * | 2016-05-12 | 2016-09-28 | 宁夏思科达生物科技有限公司 | 盐酸二甲双胍的合成方法 |
CN110256299A (zh) * | 2019-07-25 | 2019-09-20 | 凯莱英生命科学技术(天津)有限公司 | 盐酸二甲双胍的制备方法 |
CN112028795A (zh) * | 2020-09-17 | 2020-12-04 | 重庆医药高等专科学校 | 一种盐酸二甲双胍的合成方法 |
CN113248409A (zh) * | 2021-05-21 | 2021-08-13 | 海南海力制药有限公司 | 盐酸二甲双胍的合成方法及应用 |
Non-Patent Citations (2)
Title |
---|
CHEN ZHANGUO, WANG SHU-XIN, LIU QIAN-GUANG, HE HUAI-GUO: "Selection of Best Condition in Synthetic Process of Metformin Hydrochloride and a New Approach for Improving Product′s Purity", JOURNAL OF SHAANXI NORMAL UNIVERSITY (NATURAL SCIENCE EDITION), vol. 29, no. 4, 31 December 2001 (2001-12-31), pages 84 - 86, XP093006183, ISSN: 1001-3857 * |
XIONG YANG, SONG WANTONG, SHEN LIMEI, WANG YING, ZHANG JING, HU MENGYING, LIU YUN, LI JINGJING, MUSETTI SARA, LIU RIHE, HUANG LEAF: "Oral Metformin and Polymetformin Reprogram Immunosuppressive Microenvironment and Boost Immune Checkpoint Inhibitor Therapy in Colorectal Cancer", ADVANCED THERAPEUTICS, WILEY, vol. 3, no. 12, 1 December 2020 (2020-12-01), pages 2000168, XP093006174, ISSN: 2366-3987, DOI: 10.1002/adtp.202000168 * |
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