Synthesis method of amidinotaurine

Abstract

The invention discloses a synthesis method of amidinotaurine, which comprises the following steps: by taking thiourea and sulfonate as initial raw materials, carrying out heating reaction in a water phase system to generate S-alkyl thiourea sulfonate, then adding taurine, carrying out substitution reaction to generate amidinotaurine, regulating the pH value of the system to alkalescence, cooling, crystallizing and separating to obtain the amidinotaurine. According to the synthesis method of the amidinotaurine, the amidinotaurine is synthesized by taking water as a reaction medium and taking thiourea, sulfonate and taurine as raw materials through a one-pot method, the raw material cost is low, and the economic benefit is good; according to the method, the reaction speed of the product can be increased, the separation and purification operation is simplified, the production efficiency can be improved, and the obtained amidinotaurine is high in yield and purity and has market popularization value.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical intermediate preparation, in particular to a method for synthesizing amidinotaurine. Background Art

[0002] Guanidinoethyl sulfonate (CAS: 543-18-0) is a white crystal or crystalline powder with a molecular formula of C 3 H 9 N 3 O 3 S is an important medicine and food additive. As a drug additive, guanyl taurine has the effects of lowering blood pressure, lowering blood sugar, anti-virus and anti-cancer; as a food additive and nutritional enhancer, it has the effect of improving body endurance, stamina and exercise capacity. The market demand for guanyl taurine will gradually expand, and the market prospects are good.

[0003] At present, there are mainly two methods for the synthesis of amidinotaurine:

[0004] 1) Cyanamide synthesis method:

[0005]

[0006] Chinese patents CN201210115964.1 and CN201410199916.4 both report methods for synthesizing amidinotaurine by heating taurine and cyanamide as raw materials to produce an addition reaction. However, during the heating process, cyanamide polymerizes to form dicyandiamide, which inhibits the formation of amidinotaurine.

[0007] 2) Thiourea synthesis method:

[0008]

[0009] Chinese patent CN201110394076.3 reports a method of first using thiourea and ethyl bromide to react to generate S-ethyl thiourea hydrobromide, which then reacts with taurine under alkaline conditions to synthesize amidino taurine. Among them, the raw material ethyl bromide has a boiling point of only 38°C and is very volatile, so the operating process requires high requirements and has great safety hazards.

[0010] In view of the broad market prospects of amidinotaurine, it is very urgent and meaningful to find an ideal synthesis method to overcome the shortcomings of the original synthesis process, realize product industrialization and meet market demand. Summary of the invention

[0011] The present invention can solve the above-mentioned shortcomings existing in the existing amidinotaurine production technology by providing a synthesis method of amidinotaurine.

[0012] In order to solve the above technical problems, the present invention provides a method for synthesizing guanyltaurine, which takes thiourea and sulfonic acid ester as starting materials, heats and reacts in an aqueous phase system to generate S-alkylthiourea sulfonate, then adds taurine, generates guanyltaurine through a substitution reaction, adjusts the pH value of the system to weak alkalinity, cools and crystallizes, and separates and obtains the guanyltaurine.

[0013] In a preferred embodiment of the present invention, the molar ratio of thiourea, sulfonate and taurine is 1-1.2:1-1.2:1.

[0014] In a preferred embodiment of the present invention, the temperature of the heating reaction is 80-100°C.

[0015] In a preferred embodiment of the present invention, the temperature of the substitution reaction is 60-100°C.

[0016] In a preferred embodiment of the present invention, the temperature of the substitution reaction is 65-85°C.

[0017] In a preferred embodiment of the present invention, the pH value is 7-8.

[0018] In a preferred embodiment of the present invention, the structural formula of the sulfonate is:

[0019]

[0020] Wherein, R is an aliphatic group, including at least one of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, hexyl, heptyl, octyl, nonyl, decyl, benzyl, p-fluorobenzyl, p-chlorobenzyl, p-bromobenzyl, p-methylbenzyl or p-methoxybenzyl;

[0021] R' is at least one of methyl, ethyl, propyl, isopropyl, n-butyl, trifluoromethyl, perfluorobutyl, perfluoropentyl, perfluorohexyl, phenyl, p-tolyl, p-fluorophenyl, p-chlorophenyl, p-bromophenyl, p-nitrophenyl, 1-naphthyl or 2-naphthyl.

[0022] In a preferred embodiment of the present invention, R is at least one of methyl, ethyl, n-butyl or benzyl.

[0023] In a preferred embodiment of the present invention, the R' is at least one of methyl, ethyl, trifluoromethyl or phenyl.

[0024] The beneficial effects of the present invention are as follows: the present invention provides a method for synthesizing guanyltaurine, uses water as a reaction medium, uses thiourea, sulfonic acid ester and taurine as raw materials, and synthesizes guanyltaurine in a "one-pot method", has low raw material cost and good economic benefits; the present invention can increase the reaction speed of the product, simplify separation and purification operations, and improve production efficiency; the obtained guanyltaurine has a high yield and high purity, and has market promotion value. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 is the nuclear magnetic spectrum of the amidinotaurine prepared by the present invention;

[0026] Figure 2 It is the mass spectrum of the amidinotaurine prepared by the present invention. DETAILED DESCRIPTION

[0027] The preferred embodiments of the present invention are described in detail below in conjunction with the accompanying drawings so that the advantages and features of the present invention can be more easily understood by those skilled in the art, thereby making a clearer and more definite definition of the protection scope of the present invention.

[0028] The present invention uses cheap and readily available thiourea and sulfonic acid ester as starting materials, firstly heats and reacts in an aqueous phase system to generate S-alkylthiourea sulfonate, then the obtained S-alkylthiourea sulfonate undergoes a substitution reaction with added taurine to generate the target product guanyltaurine, and finally adjusts the pH value of the system to 7-8, cools and crystallizes, and separates and obtains the guanyltaurine. The entire synthetic route is as follows:

[0029]

[0030] The above-mentioned synthesis method has mild reaction conditions, simple and convenient operation, and the obtained target product amidinotaurine has high purity and high yield, and is suitable for industrial scale-up production.

[0031] Specifically, the molar ratio of thiourea, sulfonate and taurine is 1-1.2:1-1.2:1.

[0032] The temperature of the heating reaction is 80-100°C.

[0033] The temperature of the substitution reaction is 60-100°C, preferably 65-85°C.

[0034] In the structural formula of the sulfonate, R is an aliphatic group, including at least one of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, hexyl, heptyl, octyl, nonyl, decyl, benzyl, p-fluorobenzyl, p-chlorobenzyl, p-bromobenzyl, p-methylbenzyl or p-methoxybenzyl; preferably at least one of methyl, ethyl, n-butyl or benzyl.

[0035] R' is at least one of methyl, ethyl, propyl, isopropyl, n-butyl, trifluoromethyl, perfluorobutyl, perfluoropentyl, perfluorohexyl, phenyl, p-tolyl, p-fluorophenyl, p-chlorophenyl, p-bromophenyl, p-nitrophenyl, 1-naphthyl or 2-naphthyl; preferably at least one of methyl, ethyl, trifluoromethyl or phenyl.

[0036] The synthesis process of the present invention is described in detail below through specific examples.

[0037] Example 1

[0038] Add 76 g of thiourea, 178 g of ethyl trifluoromethanesulfonate and 500 ml of water to the reaction bottle, and heat to reflux for 45 minutes under the condition of rapid stirring at 300 r / min. Cool to 50°C, add 125 g of taurine to the reaction bottle, heat to 80°C, react at constant temperature for 1 hour, cool to room temperature, adjust the pH value of the system to 7.5 with 15wt% ammonia water, continue to cool to 5°C, stir and crystallize, filter, wash with ice water twice, recrystallize the obtained solid with drinking pure water, filter and dry, and obtain 154 g of product with a yield of 92%, melting point: 264-265°C; 1HNMR (D2O, 400MHz): 3.29 (t, J=6.6Hz, 2H), 3.12 (t, J=6.6Hz, 2H); M+H=168.0.

[0039] Example 2

[0040] 76 g of thiourea, 110 g of methyl methanesulfonate and 450 ml of water were added to a reaction flask, heated to 80° C. under rapid stirring at 300 r / min, and reacted at a constant temperature for 30 minutes; cooled to 50° C., 125 g of taurine was added to the reaction flask, and then heated to 60° C., and reacted at a constant temperature for 1 hour, cooled to room temperature, and the pH value of the system was adjusted to 7.2 with 15 wt % ammonia water, and continued to cool to 5° C., stirred for crystallization, filtered, and washed with ice water twice. The obtained solid was recrystallized with drinking purified water, filtered, and dried to obtain 155 g of product with a yield of 93%. The characterization test data was the same as in Example 1.

[0041] Example 3

[0042] 76 g of thiourea, 172 g of methyl benzenesulfonate and 500 ml of water were added to a reaction flask, and the mixture was heated to reflux for reaction for 45 minutes under rapid stirring at 300 r / min; the mixture was cooled to 50° C., 125 g of taurine was added to the reaction flask, the mixture was heated to 60° C., the mixture was reacted at a constant temperature for 1 hour, the mixture was cooled to room temperature, the pH value of the system was adjusted to 7.8 using 15 wt % ammonia water, the mixture was further cooled to 5° C., the mixture was stirred for crystallization, filtered, and washed with ice water twice. The obtained solid was recrystallized using pure drinking water, filtered, and dried to obtain 157 g of the product with a yield of 95%. The characterization test data was the same as in Example 1.

[0043] Example 4

[0044] 38 g of thiourea, 100 g of benzyl methanesulfonate and 500 ml of water were added to a reaction flask, and the mixture was heated to reflux for reaction for 2 hours under rapid stirring at 300 r / min; the mixture was cooled to 50° C., 62 g of taurine was added, the mixture was heated to 100° C. for reaction for 2 hours, the mixture was cooled to room temperature, the pH value of the system was adjusted to 7.5 using 15 wt % ammonia water, the mixture was further cooled to 5° C., the mixture was stirred for crystallization, filtered, and washed with ice water twice. The obtained solid was recrystallized using pure drinking water, filtered, and dried to obtain 75 g of the product with a yield of 90%. The characterization test data was the same as in Example 1.

[0045] Example 5

[0046] 3.8 kg of thiourea, 8.6 kg of methyl benzenesulfonate and 25 liters of water were added to a 50-liter low-temperature reactor, and heated to reflux for reaction for 1 hour under a rapid stirring condition of 300 r / min; the heating was stopped, and after cooling to no reflux, 6.3 kg of taurine was added, and the mixture was heated to 80° C. and reacted at a constant temperature for 1 hour, cooled to about 20° C., and the pH value of the system was adjusted to 7.2 using 15wt% ammonia water, and further cooled to 5° C., stirred for crystallization for 2 hours, filtered, washed with ice water twice, and the solid was recrystallized using drinking pure water, filtered and dried to obtain 8 kg of product with a yield of 96%. The characterization test data was the same as in Example 1.

[0047] The above descriptions are merely embodiments of the present invention and are not intended to limit the patent scope of the present invention. Any equivalent structure or equivalent process transformation made using the contents of the present invention specification and drawings, or directly or indirectly applied in other related technical fields, are also included in the patent protection scope of the present invention.

Claims

1. A method for synthesizing amidinotaurine, characterized in that: Thiourea and sulfonic acid ester are used as starting materials, and S-alkylthiourea sulfonate is generated by heating reaction in an aqueous phase system. Taurine is then added to generate guanyltaurine through a substitution reaction. The pH value of the system is adjusted to weak alkalinity, and the system is cooled for crystallization to separate and obtain the guanyltaurine.

2. The method for synthesizing amidinotaurine according to claim 1, characterized in that: The molar ratio of the thiourea, sulfonic acid ester and taurine is 1-1.2:1-1.2:

1.

3. The method for synthesizing amidinotaurine according to claim 1, characterized in that: The temperature of the heating reaction is 80-100°C.

4. The method for synthesizing amidinotaurine according to claim 1, characterized in that: The temperature of the substitution reaction is 60-100°C.

5. The method for synthesizing amidinotaurine according to claim 4, characterized in that: The temperature of the substitution reaction is 65-85°C.

6. The method for synthesizing amidinotaurine according to claim 1, characterized in that: The pH value is 7-8.

7. The method for synthesizing amidinotaurine according to claim 1, characterized in that: The structural formula of the sulfonate is: Wherein, R is an aliphatic group, including at least one of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, hexyl, heptyl, octyl, nonyl, decyl, benzyl, p-fluorobenzyl, p-chlorobenzyl, p-bromobenzyl, p-methylbenzyl or p-methoxybenzyl; R' is at least one of methyl, ethyl, propyl, isopropyl, n-butyl, trifluoromethyl, perfluorobutyl, perfluoropentyl, perfluorohexyl, phenyl, p-tolyl, p-fluorophenyl, p-chlorophenyl, p-bromophenyl, p-nitrophenyl, 1-naphthyl or 2-naphthyl.

8. The method for synthesizing amidinotaurine according to claim 7, characterized in that: The R is at least one of a methyl group, an ethyl group, a n-butyl group or a benzyl group.

9. The method for synthesizing amidinotaurine according to claim 7, characterized in that: The R' is at least one of methyl, ethyl, trifluoromethyl or phenyl.

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