CN115894306A - Preparation method of N-N-butylsulfonyl-L-tyrosine methyl ester - Google Patents
Preparation method of N-N-butylsulfonyl-L-tyrosine methyl ester Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- 238000006243 chemical reaction Methods 0.000 claims abstract description 38
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 36
- 238000000034 method Methods 0.000 claims abstract description 29
- MWZPENIJLUWBSY-VIFPVBQESA-N methyl L-tyrosinate Chemical compound COC(=O)[C@@H](N)CC1=CC=C(O)C=C1 MWZPENIJLUWBSY-VIFPVBQESA-N 0.000 claims abstract description 24
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims abstract description 22
- 239000002253 acid Substances 0.000 claims abstract description 22
- 239000007810 chemical reaction solvent Substances 0.000 claims abstract description 22
- 150000003839 salts Chemical class 0.000 claims abstract description 21
- 239000011230 binding agent Substances 0.000 claims abstract description 19
- WEDIIKBPDQQQJU-UHFFFAOYSA-N butane-1-sulfonyl chloride Chemical compound CCCCS(Cl)(=O)=O WEDIIKBPDQQQJU-UHFFFAOYSA-N 0.000 claims abstract description 16
- 238000005694 sulfonylation reaction Methods 0.000 claims abstract description 13
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims abstract description 11
- 238000005576 amination reaction Methods 0.000 claims abstract description 8
- 230000006103 sulfonylation Effects 0.000 claims abstract description 7
- 239000011259 mixed solution Substances 0.000 claims description 18
- 230000008569 process Effects 0.000 claims description 12
- HWAAPJPFZPHHBC-FGJQBABTSA-N tirofiban hydrochloride Chemical compound O.Cl.C1=CC(C[C@H](NS(=O)(=O)CCCC)C(O)=O)=CC=C1OCCCCC1CCNCC1 HWAAPJPFZPHHBC-FGJQBABTSA-N 0.000 claims description 9
- 229960004929 tirofiban hydrochloride Drugs 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 229940124530 sulfonamide Drugs 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- 229960004441 tyrosine Drugs 0.000 claims description 4
- 239000002516 radical scavenger Substances 0.000 claims description 3
- 150000003456 sulfonamides Chemical class 0.000 claims description 3
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 claims description 2
- 230000008901 benefit Effects 0.000 abstract description 9
- 238000009776 industrial production Methods 0.000 abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 239000000243 solution Substances 0.000 description 14
- 239000000047 product Substances 0.000 description 10
- 238000002474 experimental method Methods 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- 230000035484 reaction time Effects 0.000 description 5
- 230000000694 effects Effects 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 230000001737 promoting effect Effects 0.000 description 3
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000013146 percutaneous coronary intervention Methods 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- XHFLOLLMZOTPSM-UHFFFAOYSA-M sodium;hydrogen carbonate;hydrate Chemical class [OH-].[Na+].OC(O)=O XHFLOLLMZOTPSM-UHFFFAOYSA-M 0.000 description 2
- NVBFHJWHLNUMCV-UHFFFAOYSA-N sulfamide Chemical compound NS(N)(=O)=O NVBFHJWHLNUMCV-UHFFFAOYSA-N 0.000 description 2
- 206010002388 Angina unstable Diseases 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 208000007814 Unstable Angina Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000004134 energy conservation Methods 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 201000004332 intermediate coronary syndrome Diseases 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000036632 reaction speed Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
Abstract
The invention provides a preparation method of N-N-butylsulfonyl-L-tyrosine methyl ester, which comprises the following steps: carrying out sulfonylation amination reaction on N-butylsulfonyl chloride and L-tyrosine methyl ester or salt thereof in a reaction solvent containing an acid-binding agent to obtain the N-N-butylsulfonyl-L-tyrosine methyl ester, wherein the reaction solvent is selected from dichloromethane, and the acid-binding agent is selected from pyridine. The method for preparing the N-N-butylsulfonyl-L-tyrosine methyl ester has the advantages of low reaction temperature, short time consumption, high yield, high purity, simple post-treatment and the like, and is suitable for industrial production and application.
Description
Technical Field
The present invention relates to the field of medicine. In particular, the invention relates to a method for preparing N-N-butylsulfonyl-L-tyrosine methyl ester.
Background
Tirofiban hydrochloride (with a structure shown in formula I) has high selectivity and specificity on platelet IIb/IIIa receptors, reversibly inhibits platelet aggregation, and is currently used for treating unstable angina or non-Q wave myocardial infarction patients with heparin and preventing cardiac ischemia in Percutaneous Coronary Intervention (PCI).
The currently known preparation process of tirofiban hydrochloride basically involves a sulfonylation process, an ether forming process, a hydrolysis process, a hydrogenation process, a salt forming process and the like. The reaction yield and purity of the sulfonylation step as the initial reaction are very important for the yield and purity of the tirofiban hydrochloride production process.
However, the existing sulfonylation amination process has the defects of low yield, low purity, high reaction temperature, long use time and the like, and restricts the production and application of tirofiban hydrochloride.
Disclosure of Invention
The invention aims to solve the technical problems in the prior art at least to a certain extent, and provides a preparation method of N-N-butylsulfonyl-L-tyrosine methyl ester.
In one aspect of the invention, the invention provides a preparation method of N-N-butylsulfonyl-L-tyrosine methyl ester. According to an embodiment of the invention, the method comprises: carrying out sulfonylation reaction on N-butylsulfonyl chloride and L-tyrosine methyl ester or salt thereof in a reaction solvent containing an acid-binding agent to obtain the N-N-butylsulfonyl-L-tyrosine methyl ester, wherein the reaction solvent is selected from dichloromethane, and the acid-binding agent is selected from pyridine (an exemplary reaction formula is shown as below).
During the research process, the inventor finds that the type of the reaction solvent of the n-butylsulfonyl chloride and the L-tyrosine methyl ester or the salt thereof can significantly influence the temperature and the time of the sulfonylation reaction, and further influence the yield and the purity. Furthermore, the inventors have found through a large number of experiments that the use of dichloromethane as a reaction solvent can lower the reaction temperature, shorten the reaction time, and contribute to the improvement of the yield and purity. Further, the inventors have unexpectedly found that the difference between the action effect of dichloromethane and that of different acid-binding agents is large, for example, if sodium bicarbonate and potassium carbonate are used as the acid-binding agents, the reaction is incomplete, and the yield is low; when triethylamine, 4-dimethylaminopyridine and diisopropylethylamine are used as acid-binding agents, the yield reaches about 50%, and the purity reaches about 80%; when pyridine is used as an acid-binding agent, the pyridine is in homogeneous reaction, the reaction is complete, impurities are few, and the reaction effect is good, so the pyridine is preferably used as the acid-binding agent. Therefore, the method provided by the embodiment of the invention has the advantages of low reaction temperature, short time consumption, high yield, high purity, simple post-treatment and the like, and is suitable for industrial production and application.
According to the embodiment of the invention, the preparation method of N-N-butylsulfonyl-L-tyrosine methyl ester can also have the following additional technical characteristics:
according to an embodiment of the present invention, the molar ratio of n-butylsulfonyl chloride to L-tyrosine methyl ester or a salt thereof is (0.9 to 1.1): 1. the inventor obtains the better proportion through a large amount of experiments, thereby promoting the generation of the sulfamide reaction and reducing the generation of byproducts. In some embodiments, the molar ratio of n-butylsulfonyl chloride to L-tyrosine methyl ester or salt thereof is (1 to 1.05): 1, preferably (1.01 to 1.03): 1.
according to an embodiment of the present invention, the molar ratio of the acid scavenger to the L-tyrosine methyl ester or salt thereof is (2 to 3): 1. the inventor obtains the better proportion through a large amount of experiments, thereby promoting the positive progress of the sulfamide reaction and improving the yield and the purity of the product. In some embodiments, the molar ratio of the acid scavenger to the L-tyrosine methyl ester or salt thereof is (2-2.7): 1, preferably (2 to 2.6): 1.
according to an embodiment of the present invention, the mass ratio of the reaction solvent to the L-tyrosine methyl ester or salt thereof may be (5 to 30): 1. the inventor obtains the better proportion through a large amount of experiments, thereby promoting the positive progress of the sulfonylation amination reaction, improving the yield and the purity of the product, and reducing the reaction temperature and the reaction time. In some embodiments, the mass ratio of the reaction solvent to the L-tyrosine methyl ester or salt thereof is (10 to 20): 1.
according to an embodiment of the present invention, the preparation method further comprises the steps of: and dropwise adding the n-butylsulfonyl chloride into the mixed solution of the L-tyrosine methyl ester, the acid-binding agent and the reaction solvent to perform the sulfonamide amination reaction. Further, the temperature of the mixed solution was controlled to be not higher than 10 ℃ at the time of dropwise addition.
According to an embodiment of the present invention, the preparation method further comprises: (1) Mixing the acid-binding agent, L-tyrosine methyl ester or salt thereof and part of the reaction solvent to obtain a first mixed solution; (2) And dropwise adding the rest of the reaction solvent containing the N-butylsulfonyl chloride into the first mixed solution to perform the sulfonylation reaction to obtain the N-N-butylsulfonyl-L-tyrosine methyl ester.
According to the embodiment of the invention, before the first mixed solution is subjected to the step (2), the temperature of the first mixed solution is reduced to be not higher than 5 ℃; in the dropping process, the temperature of the first mixed solution is not higher than 10 ℃.
According to an embodiment of the invention, the reaction temperature of the sulphonamide amination reaction is between 20 and 30 ℃.
According to an embodiment of the present invention, the reaction time of the sulfonylation reaction may be 4 to 6 hours.
The inventor obtains the better reaction temperature and time through a large number of experiments, so that the reaction can be carried out at room temperature (20-30 ℃) for a short time, side reactions caused by long-time high-temperature reaction can be avoided to a certain extent, the yield and the purity are improved, and the preparation efficiency is integrally improved.
According to an embodiment of the present invention, the reaction solution obtained by the sulfonylation reaction is post-treated as follows: carrying out reduced pressure concentration on the reaction liquid to obtain a concentrate; dissolving the concentrate with ethyl acetate, washing the concentrate with a dilute hydrochloric acid solution, a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride solution respectively, collecting an organic layer for washing next time, drying the finally obtained organic layer with anhydrous sodium sulfate, filtering, washing an obtained filter cake with ethyl acetate, and concentrating the obtained filtrate to obtain the N-N-butylsulfonyl-L-tyrosine methyl ester. The post-treatment method is simple and convenient to operate, and can efficiently remove impurities and improve the purity and yield of the product.
According to an embodiment of the invention, the preparation method of N-N-butylsulfonyl-L-tyrosine methyl ester comprises the following steps:
(1) Mixing pyridine, L-tyrosine methyl ester or salt thereof and partial dichloromethane to obtain a first mixed solution, and reducing the temperature of the first mixed solution to be not higher than 5 ℃;
(2) Dropwise adding the residual dichloromethane containing N-butylsulfonyl chloride into the first mixed solution, controlling the temperature of the first mixed solution to be not higher than 10 ℃, and after dropwise adding is completed, performing sulfonamide reaction for 4-6 hours at 20-30 ℃ to obtain the N-N-butylsulfonyl-L-tyrosine methyl ester;
wherein, the molar ratio of the n-butylsulfonyl chloride to the L-tyrosine methyl ester or the salt thereof is (1.01-1.03): 1, the molar ratio of pyridine to L-tyrosine methyl ester or salt thereof is (2-2.6): 1, the mass ratio of the total amount of the dichloromethane to the L-tyrosine methyl ester or the salt thereof is (10-20): 1.
therefore, the yield and the purity of the N-N-butylsulfonyl-L-tyrosine methyl ester can be effectively improved, the reaction time is shortened, the reaction speed is reduced, and the production efficiency is integrally improved.
In another aspect of the invention, the invention provides a preparation of N-N-butylsulfonyl-L-tyrosine methyl ester. According to an embodiment of the invention, the preparation of methyl N-N-butylsulfonyl-L-tyrosine is obtained by the above method for preparing methyl N-N-butylsulfonyl-L-tyrosine. Therefore, the N-N-butylsulfonyl-L-tyrosine methyl ester product provided by the embodiment of the invention has the advantage of high purity, and the application value of the product can be improved, for example, the product can be applied to the preparation of tirofiban hydrochloride.
It should be noted that the features and advantages described above for the preparation of N-N-butylsulfonyl-L-tyrosine methyl ester are also applicable to the N-N-butylsulfonyl-L-tyrosine methyl ester preparation, and are not described herein again.
In another aspect of the invention, the invention provides a preparation method of tirofiban hydrochloride. According to an embodiment of the invention, the method comprises: N-N-butylsulfonyl-L-tyrosine methyl ester was prepared as described previously. As mentioned above, the N-N-butylsulfonyl-L-tyrosine methyl ester product has the advantage of high purity, so that the tirofiban hydrochloride prepared by the N-N-butylsulfonyl-L-tyrosine methyl ester product also has the advantage of high purity, and the preparation method is simple and convenient to operate, low in cost and suitable for industrial production.
It should be noted that the characteristics and advantages described above for the N-butylsulfonyl-L-tyrosine methyl ester preparation are also applicable to the tirofiban hydrochloride preparation method, and are not described herein again.
The invention has the beneficial technical effects that: the preparation method of the N-N-butylsulfonyl-L-tyrosine methyl ester adopts N-butylsulfonyl chloride and L-tyrosine methyl ester or salt thereof as raw materials to carry out sulfonylation amination reaction, adopts dichloromethane as a reaction solvent, adopts pyridine as an acid-binding agent, can carry out reaction at room temperature, greatly shortens the reaction time, improves the yield by over 80 percent, improves the purity by over 90 percent, and is suitable for industrial production through KG-level production process verification. Compared with the existing preparation method of N-N-butylsulfonyl-L-tyrosine methyl ester, the method has the advantages of high reaction efficiency, energy conservation and important industrial significance.
Additional aspects and advantages of the invention will be set forth in part in the description which follows and, in part, will be obvious from the description, or may be learned by practice of the invention.
Detailed Description
The scheme of the invention will be explained with reference to the examples. It will be appreciated by those skilled in the art that the following examples are illustrative of the invention only and should not be taken as limiting the scope of the invention. The examples do not specify particular techniques or conditions, and are performed according to techniques or conditions described in literature in the art or according to the product specification. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.
Example 1
N-N-butylsulfonyl-L-tyrosine methyl ester was prepared using the following method:
mixing an acid-binding agent, L-tyrosine methyl ester and part of reaction solvent to obtain a mixed solution, cooling to below 5 ℃, dropwise adding the reaction solvent containing n-butylsulfonyl chloride into the mixed solution, and controlling the temperature of the mixed solution to be below 10 ℃. The temperature is increased to carry out the reaction, and the TLC monitors the reaction end point.
After the reaction is finished, concentrating the reaction solution under reduced pressure, dissolving the concentrated solution by using ethyl acetate, washing by using a dilute hydrochloric acid solution, a saturated sodium bicarbonate water solution and a saturated sodium chloride solution respectively, layering to obtain an organic layer, drying by using anhydrous sodium sulfate, filtering, washing a filter cake by using ethyl acetate, concentrating the filtrate to obtain N-N-butylsulfonyl-L-tyrosine methyl ester, and storing at the temperature of below 10 ℃.
The reaction parameters and the reaction results are shown in Table 1. It can be seen that the yield and purity of the N-N-butylsulfonyl-L-tyrosine methyl ester obtained by the experimental group are superior to those of the comparative group, and the difference between the experimental group and the comparative group is mainly the difference between the acid-binding agent and the reaction solvent, so that the pyridine (acid-binding agent) and the dichloromethane (reaction solvent) are matched with each other to achieve the optimal use effect, and the yield and the purity can be effectively improved.
TABLE 1 reaction parameters and reaction results
Note: " ※ "indicates that the reaction was not completed at 20 hours, room temperature was 20-30 ℃.
Example 2
32kg of methylene chloride (376.8 mol), 2.3kg of pyridine (29.1 mol) and 2.2kg of L-tyrosine methyl ester (11.3 mol) were put into a reaction vessel, stirred and cooled to 5 ℃ or less, and 1.78kg of a methylene chloride solution (4.0 kg,47.1 mol) of n-butylsulfonyl chloride (11.4 mol) was added dropwise thereto and mixed into the reaction vessel, and the temperature was controlled to 10 ℃ or less. The temperature is increased to 20-30 ℃ for 5 hours of reaction, and the end point of the reaction is monitored by TLC. After the reaction, the reaction solution is concentrated under reduced pressure, ethyl acetate is used for dissolving the concentrated solution, then diluted hydrochloric acid solution, saturated sodium bicarbonate water solution and saturated sodium chloride solution are respectively used for washing, an organic layer is obtained by layering, anhydrous sodium sulfate is used for drying, filtering is carried out, a filter cake is washed by about 1.0kg of ethyl acetate, and filtrate is concentrated to obtain 3.18kg of N-N-butylsulfonyl-L-tyrosine methyl ester which is preserved at the temperature of below 10 ℃, the yield is 89.3%, and the purity is 94.1%.
The experiment is to amplify the process, can still realize the production of the N-N-butylsulfonyl-L-tyrosine methyl ester at normal temperature, has high yield, high purity and short time consumption, and is suitable for industrial production.
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.
Claims (10)
1. A preparation method of N-N-butylsulfonyl-L-tyrosine methyl ester is characterized by comprising the following steps:
carrying out sulfonylation amination reaction on N-butylsulfonyl chloride and L-tyrosine methyl ester or salt thereof in a reaction solvent containing an acid binding agent to obtain the N-N-butylsulfonyl-L-tyrosine methyl ester,
wherein the reaction solvent is selected from dichloromethane, and the acid-binding agent is selected from pyridine.
2. The process according to claim 1, wherein the molar ratio of n-butylsulfonyl chloride to L-tyrosine methyl ester or a salt thereof is (0.9 to 1.1): 1, further (1 to 1.05): 1, further (1.01 to 1.03): 1.
3. the method of claim 1, wherein the molar ratio of the acid scavenger to the L-tyrosine methyl ester or salt thereof is (2-3): 1, further (2 to 2.7): 1, further (2 to 2.6): 1.
4. the method according to claim 1, wherein the mass ratio of the reaction solvent to the L-tyrosine methyl ester or the salt thereof is (5-30): 1, further may be (10 to 20): 1.
5. the process according to claim 1, characterized in that the temperature of the sulphonamide reaction is between 20 and 30 ℃.
6. The method of claim 1, wherein the method of making further comprises the steps of: and dropwise adding the n-butylsulfonyl chloride into the mixed solution of the L-tyrosine methyl ester, the acid-binding agent and the reaction solvent to perform the sulfonamide amination reaction.
7. The method of claim 6, further comprising:
(1) Mixing the acid-binding agent, L-tyrosine methyl ester or salt thereof and part of the reaction solvent to obtain a first mixed solution;
(2) And dropwise adding the rest of the reaction solvent containing the N-butylsulfonyl chloride into the first mixed solution to perform the sulfonylation reaction to obtain the N-N-butylsulfonyl-L-tyrosine methyl ester.
8. The method of claim 7, wherein prior to subjecting the first mixed liquor to step (2), the first mixed liquor is cooled to a temperature of no more than 5 ℃;
in the dropwise adding process, the temperature of the first mixed solution is not higher than 10 ℃.
9. A product of methyl N-N-butylsulfonyl-L-tyrosine obtained by the process for producing methyl N-N-butylsulfonyl-L-tyrosine according to any one of claims 1 to 8.
10. A preparation method of tirofiban hydrochloride is characterized by comprising the following steps: N-N-butylsulfonyl-L-tyrosine methyl ester is prepared by the method of any one of claims 1 to 8.
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2021
- 2021-09-24 CN CN202111123281.6A patent/CN115894306A/en active Pending
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