TW518337B - Method for the preparation of pure carboxyethyl germanium sesquioxide - Google Patents

Abstract

This invention provides a method for synthesizing pure carboxyethyl germanium sesquioxide that does not include any toxic impurities, such as germanium dioxide or metallic germanium. Neither of these toxic compounds is used as a starting material. The method involves steps which ensure the full reaction of germanium tetrachloride in order to ensure that none is available to form germanium dioxide and steps which ensure the removal of any germanium dioxide.

Description

518337 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Invention Description (6) ch3 ch3 ί! GeCl4 + HSi-OSiH + H2C = C-C02H ........... ί I CH3 ch3 h Η H!! Cl3Ge-C · | C-C〇2h + germanium propionate reaction product Η Η + volatile by-product (TPA) Step 2-Regarding the second step in a favorable entity, the first mixture is subjected to Vacuum distillation to remove volatile by-products. An advantageous vacuum is from about 0.1 Torr to about 25Torr, and more advantageously from about 0.5Torr to about 5To: rr. The internal temperature of this vacuum distillation is about 60 ° C to about 75 ° C. Distillation leads to a second reaction mixture consisting essentially of the reaction product of TP A plus germanium acrylate. The reaction flow in this step is Η Η CI3G--C-C-C02H ^ Distillation of the reaction product! + Volatile by-products ........ Η Η Η Η ί ι -Cl ^ Ge 'C, * VC〇2H " The reaction product of germanium propionate ti Η Τ (TPA) Step 3 In an advantageous entity, the second reaction mixture reacts with Η c 1 (please read the first (Notes on this page)

Alignment · This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) -9-Germanium Acrylic Acid Reaction Product + HC1 (Concentrated) --------- > Staff Consumption of Central Standards Bureau, Ministry of Economic Affairs Cooperative Du printed 518337 A7 _ B7 5. Description of the invention (7), the amount of the latter is at least enough to react with the reaction product of germanium acrylate so that the reaction product of germanium is converted to TPA. Therefore, in this step, a mixture of TPA and HC 1 is obtained. An advantageous amount of HC 1 is a mass comparison of about 0.25 to about 10 mass equivalents of germanium chloride), and most advantageously about 0.5 to about 3 mass equivalents. A favorable temperature for the reaction is about 60 ° C to about 85 ° C 'and a favorable time for the reaction is about 30 minutes to about 4 hours, most advantageously about 45 minutes to about 90 minutes. This result is a third mixture consisting essentially of a TP A white solid and a halogenated mixture of aqueous concentrated rhenium-C1. The reaction flow of this step is: Η Η I! C-c-co2h I j

Η H Η Κ

Cipe-C · C:-COzH + HC1 (concentrated): i 'Η Η (TPA) Step 4 In the next step in an advantageous entity, the third mixture is subjected to solvent extraction to separate hydrochloric acid from TPA, thus producing The fourth mixture consists essentially of TPA and an extraction solvent. Suitable extraction solvents in an amount sufficient to extract all of the H C 1 include halogenated solvents such as chloroform and carbon tetrachloride, and advantageously, dichloromethane. The amount of halogenated solvent used in the extraction is about 1 to about 30 mass equivalents (compared to the starting mass of germanium tetrachloride), and most preferably about 3 to about 8 mass equivalents. Advantageously use too much extraction solvent to comply with Chinese National Standard (CNS) A4 specification (210X297 mm) at this paper size. -10-Please read the back page first page 518337 A7 B7 V. Description of the invention (1〇) TPA crystals are 1 mass equivalent solvent. Steps 9 and 10 In a final step in an advantageous entity, pure τ PA crystals are then reacted under reflux conditions with a small amount of distilled water gradually added. A small amount means adding only enough distilled water to dissolve the crystals into the solution. An advantageous amount of distilled water is about 15 to about 25 mass equivalents (compared to the TPA mass). A favorable internal temperature is about 7 ° C to about 100 ° C. The reflux time is advantageously about 1 to about 3 hours. After the crystals are dissolved, the addition of distilled water is stopped, and the solution is cooled to ambient temperature and left to stand for at least about 12 hours, and most advantageously about 24 hours to 48 hours. The result is a pure germanium sesquioxide solid, which is then filtered using gravity filters or filter paper (such as Watman # 4 paper) or suction filtration (funnel type) and filter paper (such as Watman # 2 paper). The filtered solution was washed sequentially with water, acetone and, finally, ether. The water washing liquid is about 1 mass equivalent (compared to TP A) to about 10 mass equivalent, and more advantageously, about 2 to about 4 mass equivalent. The acetone wash is about 1 to about 10 mass equivalents (compared to TPA), and advantageously about 2 to about 4 mass equivalents. In the end, the ether wash is about 1 to about 10 mass equivalents (compared to TPA), and advantageously about 2 to about 4 mass equivalents. The chemical formula of pure carboxyethylgermanium sesquioxide is Ge 2C4H1Q07. The purified and isolated carboxyethylgermanium sesquioxide may then be used in, for example, a dietary supplement to give the aforementioned health benefits. One of the benefits of the carboxyethylgermanium sesquioxide process of the present invention is that it provides a safe and effective form of germanium for human use. This paper size applies to China National Standard (CNS) A4 (210X297mm) -13-(Please read the precautions on the back before

Ordered by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, printed 518337 Printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, printed by A7 B7 V. Invention Description (11) In particular, the present invention eliminates the possibility that germanium metal can enter food supplement Because the starting materials and methods do not have any potential for germanium metal. In addition, the present invention eliminates the potential for the introduction of germanium dioxide into a dietary supplement that incorporates a carboxyethylgermanium sesquioxide produced by the method of the present invention. There are two main reasons for this. First, the recrystallization step of the above method eliminates any germanium dioxide that may have been produced by any previous step. Second, the method of the invention is used to eliminate any germanium dioxide, even before the recrystallization step. In particular, any germanium dioxide present in the process of the invention will only exist as a by-product of the germanium tetrachloride used in the first reaction step. In other words, in the initial reaction of germanium tetrachloride with tetramethylethoxysilane and acrylic acid, theoretically there may be unreacted germanium tetrachloride, which can potentially hydrolyze to germanium dioxide. However, the second step of vacuum distillation removes any remaining unreacted germanium tetrachloride, thereby preventing the formation of additional germanium dioxide through hydrolysis. Even if any germanium dioxide remains in the water phase as a by-product, such germanium dioxide is removed and discarded by subsequent extraction and distillation steps of the method. For example, in the next step in the process (ie, the third step in the advantageous entity described above), the reaction with hydrochloric acid will convert any germanium dioxide by-product to germanium tetrachloride. If any germanium dioxide remains after the distillation and extraction steps, it will be observed as a solid during the next step of extraction with a solvent of a halogenated solvent, because germanium dioxide is insoluble in the halogenated solvent. Since no germanium dioxide was observed, it was clear that germanium dioxide was not present in the organic phase. Furthermore, the vacuum distillation step below will remove any germanium tetrachloride produced by the reaction of HC 1 and germanium dioxide, thereby eliminating any possibility that germanium tetrachloride or germanium dioxide remains in the reaction mixture. . As a result, the method of the present invention provides that the paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) -14-(Please read the precautions on the back before this page)

Ordering · 518337 A7 B7 V. Description of the invention (12) A sufficient carboxyethyl germanium sesquioxide product for human consumption. Please read the note below. The method for preparing carboxyethylgermanium sesquioxide according to the present invention has other advantages. For example, the present invention provides high yields of pure carboxyethylgermanium sesquioxide. "High yield" means that the yield of pure carboxyethylgermanium sesquioxide is increased by about 10% to 20% compared to the ordinary method of producing carboxyethylgermanium sesquioxide. Furthermore, It is possible that the method of the present invention can obtain a yield increase of more than 20% than the ordinary method. Another advantage of the present invention is that it avoids the use of harsh, toxic and dangerous chemicals (such as ammonium hydroxide and sulfuric acid). These systems It is used in general methods of synthesizing germanium. In addition, this method uses substantially smaller amounts of HC 1 than previously known methods, such as those described in U.S. Patent Nos. 5,504,225 and 5,386,046. As a result, the method of the present invention has ecological benefits and can save real quality time, labor and origin from the manufacturing method. The use of carboxyethylgermanium sesquioxide printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economics is also known to be beneficial to human health It is helpful. For the maintenance of daily health, a dosage range of about 10 mg / day to about 200 mg / day to about 200 mg / day is recommended. In order to treat pre-existing health conditions, such as influenza symptoms , The daily solid dosage form is About 10 mg / day to about 10,000 mg / day. For an injection solution for treating a pre-existing condition, the amount of germanium sesquioxide is about 10 mg / day to about 1,000. mg / day, and advantageously, about 30 mg / day to about 300 mg / day. The carboxyethylgermanium sesquioxide composition of the present invention is a stable compound and can be combined with other dietary supplement ingredients. These preparations can It is made by the general method. In order to prepare the composition of the present invention, according to the general mixing technology, each paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) -15-518337 A 7 __B7 V. Description of the invention (13 ) The ingredients are combined in a single preparation as the active ingredient in an intermediate blend with a suitable carrier or excipient. The composition of the present invention is compatible with commonly used excipients such as maltodextrin and microcrystalline cellulose Appropriate carriers can be used in a wide range of formulations, such as oral, sublingual, nasal or parenteral, as required. In the preparation of oral dosage forms, any general medicine can be used. Medium. For oral liquid preparations For suspensions, syrups, and solutions), media containing, for example, water, oil, alcohol, fragrance, preservatives, colorants, etc. can be used. Carriers such as starch, sugar, diluents, granulating agents, Lubricants, binders, disintegrating agents, etc. to prepare oral solids (such as powders, gelatin capsules, nine tablets, and lozenges). Gelatin capsules are advantageous oral dosage forms. Lozenges, microencapsulated lozenges, and other Controlled release. Because of ease of administration, lozenges, lozenges, capsules, and capsules represent the most advantageous oral dosage unit type, which obviously utilizes solid pharmaceutical carriers. If desired, lozenges can be sugar-coated using standard techniques For parenteral products, carriers often include sterile water, although other ingredients may be included to aid solubility or preservation purposes, for example. Injection suspensions can also be prepared, in which case suitable liquid carriers, suspending agents and the like can be utilized. As an optional entity of the above method, the following steps can be changed, where (1) the reaction time of the first step can be increased from about 7 days to between about 30 days and about 120 days, and Advantageously about 4 5 days; (2) the amount of concentrated hydrochloric acid used in the third step can be reduced; this paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) -16-please read the back first Notes

Printed by the Consumers 'Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 518337 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Invention Description (15) The solid is filtered and resuspended in 30 ml of distilled water, and then heated to reflux until the mixture Becomes uniform. This solution was then refluxed for 4 hours and then cooled to ambient temperature, whereby carboxyethylgermanium sesquioxide was formed over a period of about 48 hours. The 1-color carboxyethylgermanium sesquioxide solid was isolated by suction filtration and washed sequentially with 2x5.4 litres of acetone and 2x5.4 litres of ether. The resulting bright white carboxyethylgermanium sesquioxide solid was dried in a vacuum oven at 40 ° C overnight. Example 2 In a 50-liter glass reactor, 72 g of germanium tetrachloride, 5.3 kg of tetramethylethoxysilane, and 2.32 kg of acrylic acid were sequentially added, and the resulting reaction mixture was stirred for 5 days. The volatile by-product was removed by vacuum distillation, while the product mixture was heated to an internal temperature of 75 ° C to 80 ° C, where it was a homogeneous, colorless, semi-viscous solution (melted). Continue distillation until no more distillate appears. The reaction mixture was cooled to ambient temperature to give a white amorphous solid. This solid was then dissolved in 35 liters of concentrated H C 1. The resulting homogeneous mixture was warmed to an internal temperature of 60 ° C-70 ° C and stirred for 4 hours. The cooled mixture was extracted three times with 2.5 liters of dichloromethane. Dichloromethane was removed by vacuum distillation at 40 ° C to obtain crude TPA white amorphous solid. This TP A solid dissolved immediately (violent behavior) with careful addition of 30 liters of ammonium hydroxide (29% ammonia). The resulting mixture was stirred at ambient temperature for 4 days. To this was added 400 ml of concentrated sulfuric acid dropwise over a reflux condenser over a period of 2 hours. White T P A solids were isolated by suction filtration, and this paper size was in accordance with Chinese National Standard (CNS) Eighty-fourth Secret (210X297), 18- (Please read the precautions on the back before this page)

01T line 518337 A7 B7 5. Description of the invention (16), 2x5 · 4 liters of water, 2x5 · 4 liters of acetone and 2x5 · 4 liters of ether, and then the bright white pure TP A solid was dried by air overnight. This pure TP A solid was dissolved in 9 liters of hot distilled water, then cooled and filtered to produce carboxyethylgermanium sesquioxide. Example 3 Using an organic carboxyethylgermanium sesquioxide. An exemplary mixture of a food supplement is: ~ (Please read the precautions on the back first, then the _ page)

Pangamic Acid Carboxyethyl Germanium Sesquioxide * Co-Enzyme Q 1 0 Vitamin A Vitamin E Vitamin D Vitamin K 50 mg 2 5 mg 2 5 mg 1, 2 5 0 I 10 0 1. U 7.. 5 I. U 1 2 5 mg

U Printed by the Central Consumers Bureau of the Ministry of Economic Affairs, printed by the Consumer Cooperative of the Company * Carboxyethylgermanium sesquioxide can be prepared by any of the methods of the present invention described above. Mutations are prone to those skilled in the art, and therefore the scope of the patent application is intended to cover such modifications and equivalents. This paper size applies to China National Standard (CNS) A4 (210X297 mm) _ 19 ·

Claims (1)

Appendix A of Patent Application Scope: Patent Application No. 87 1 19493 for Chinese Patent Application Amendment? Read the notes on the back and fill it in again ^ — ^ [^ 0 ^ December Amendment 1 · ~ Preparation of substantially pure carboxylic acid Method for ethyl germanium sesquioxide, comprising the steps of: reacting germanium tetrachloride'tetramethylethoxysilane and acrylic acid to form TPA (trichlorogermanium propionate), a reaction product of germanium acrylic acid, and volatility A first reaction mixture of by-products; steaming the first reaction mixture to remove volatile by-products, thereby forming a second reaction mixture of TPA and germanium acrylate reaction products; 1 ^ 1 · reacting the second reaction mixture with HC 1 to Form a third reaction mixture of TPA and HC1;-Line · Extract halogenated C 1 from the third reaction mixture with a halogenated solvent to form a fourth reaction mixture of halogenated solvent and TP A; 'Vacuum distill the fourth reaction mixture to The halogenated solvent is removed to form a fifth reaction mixture of the crude TP A crystals; the crude TP A crystals are printed and dissolved by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. Heating in a non-polar alkyl solvent to form a sixth reaction mixture; cooling the sixth reaction mixture to form TP A crystals; filtering and washing the TP A crystals in a heated non-polar alkyl solvent to form pure T Ρ A crystal; reacting pure TP A crystal in water to form carboxyethyl germanium sesquioxide; and this paper size applies Chinese National Standard (CNS) A4 specification (210 X 297 public love) -1-518337 A8B8C8D8 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs. 6. The scope of application for patents isolates carboxyethylgermanium sesquioxide. 2. The method of claim 1 in which the first distillation step of dichlorogermanium propionic acid is vacuum distillation. Watt method of item 1 of the Li scope, the step of its rhenium reaction further includes reacting some amount of tetramethylethoxysilane and acrylic acid reactant with germanium tetrachloride to fully ensure the complete reaction of germanium tetrachloride . 4. The method of claim 1 in which the volatile by-products of the first reaction step include unreacted germanium tetrachloride, and the first reaction step further includes vacuum distillation to remove volatile by-products. 5. The method according to item 1 of the patent application, wherein the second reaction step further comprises adding some amount of hydrochloric acid, which is sufficient to ensure that any germanium dioxide reacts to germanium tetrachloride. 6. The method of claim 1 in which the extraction solvent in the extraction step includes dichloromethane. 7. The method of claim 1, further comprising the steps of observing the fourth reaction mixture for any germanium dioxide solids, and removing any such germanium dioxide present. 8. A method as claimed in claim 1 wherein the extraction step removes any remaining germanium tetrachloride. (Please read the precautions on the back before filling? F this page) I-line-This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) -2-