CN115385864A - Preparation method of threo Wo Leisheng intermediate - Google Patents
Preparation method of threo Wo Leisheng intermediate Download PDFInfo
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- CN115385864A CN115385864A CN202210955931.1A CN202210955931A CN115385864A CN 115385864 A CN115385864 A CN 115385864A CN 202210955931 A CN202210955931 A CN 202210955931A CN 115385864 A CN115385864 A CN 115385864A
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- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/08—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 not condensed with other rings
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Abstract
The invention relates to the field of drug synthesis, and discloses a preparation method of a threo Wo Leisheng intermediate, which comprises the following steps: (1) Mixing a compound of a formula II, an organic solvent and an acid, and then carrying out a tert-butyloxycarbonyl removal reaction to obtain a mixed liquid containing a compound of a formula III; (2) Mixing the mixed solution containing the compound of the formula III with alkali, performing ring closing reaction, performing primary purification to remove the alkali, adding acetonitrile, performing hot pulping, filtering while the solution is hot, concentrating, adding ethyl acetate, performing hot pulping, and filtering to obtain the compound of the formula I, namely a suvorexant intermediate. The invention adopts a one-pot method for continuous reaction and is matched with a special product purification method, so that the prepared suvorexant has higher purity while shortening the preparation flow, simplifying the process steps and improving the production efficiency.
Description
Technical Field
The invention relates to the field of drug synthesis, in particular to a preparation method of a threo Wo Leisheng intermediate.
Background
Suvorexant, chemical name 5-chloro-2- [ (5R) -5-methyl-4- [ 5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoyl ] -1,4-diazepan-1-yl ] -1,3-benzoxazole is a highly selective orexin receptor antagonist, which increases total sleep time and shortens time to sleep, improves excessive wakefulness, and does not affect sleep architecture by combining the wake-promoting neuropeptides orexin a and orexin B, selectively acting on neurons that mediate transitions between wakefulness and sleep, thereby achieving the purpose of treating insomnia and sleep disorders.
The compound shown in the formula I can be used as an organic synthesis intermediate for synthesizing high value-added compounds such as Suvorexane and the like, and fills up the important requirements which cannot be met by the current insomnia treatment market. The structural formula of the compound of formula I is as follows:
however, few reports on the synthetic method of the compound of the formula I exist at present, and a synthetic method which is simple in process and suitable for large-scale industrial production is lacked.
Disclosure of Invention
In order to solve the technical problem that the prior art lacks a synthesis method of a compound shown in formula I, which is simple in process and suitable for large-scale industrial production, the invention provides a preparation method of a Su Wo Leisheng intermediate. The method has the advantages of short preparation flow, simple process steps and suitability for large-scale production, and the high-purity suvorexant intermediate can be obtained.
The specific technical scheme of the invention is as follows:
a preparation method of a threo Wo Leisheng intermediate comprises the following steps:
(1) Mixing a compound of a formula II, an organic solvent and acid, and then carrying out a tert-butyloxycarbonyl removal reaction to obtain a mixed solution containing a compound of a formula III; the reaction route is as follows:
(2) Mixing the mixed solution containing the compound of the formula III with alkali, performing ring closing reaction, performing primary purification to remove the alkali, adding acetonitrile, performing hot pulping, filtering while the mixture is hot, concentrating, adding ethyl acetate, performing hot pulping, and filtering to obtain a compound of the formula I, namely a Suvorexant intermediate; the reaction route is as follows:
the invention takes a compound shown in a formula II (which can be prepared by adopting a conventional method and carrying out a condensation reaction on 2- (benzyl amino) methyl acetate and 3- ((tert-butyloxycarbonyl) amino) butyric acid) as raw materials, and prepares a suvorexant intermediate (the compound shown in the formula I) through a 'one-pot' continuous reaction. In the process of the continuous reaction of the 'one-pot method', after the compound of the formula II is subjected to the tert-butyloxycarbonyl removal reaction to generate the compound of the formula III (step (1)), the intermediate product (the compound of the formula III) is not separated and purified, and the alkali is directly added into the mixed solution to carry out the ring closure reaction (step (2)), so that the preparation process can be shortened, the process steps can be simplified, the production efficiency can be greatly improved, the method is suitable for large-scale industrial production, and in addition, the loss of the intermediate product in the separation and purification process can be avoided, so that the yield is improved.
The present inventors have paid attention to the fact that when a "one-pot" continuous reaction is adopted, a small amount of raw material (compound of formula II) may not be completely reacted after the t-butoxycarbonyl removal reaction in step (1), and ester hydrolysis may occur under the action of alkali after the contact with alkali in step (2) to form by-products, which are difficult to remove by conventional purification methods, resulting in poor quality and low purity of the finally obtained compound of formula I. Therefore, the purification process is specially designed based on theoretical research and experiments, and the by-product generated by the hydrolysis of the compound ester shown in the formula II can be effectively removed by adopting a purification method of acetonitrile hot beating, so that the finally prepared compound shown in the formula I has higher purity; meanwhile, the acetonitrile hot beating purification method is adopted, so that the loss of the compound in the formula I in the purification process can be reduced, and the higher yield is realized; and after the acetonitrile is subjected to hot beating, the acetonitrile can be recovered, so that the three wastes generated in the production process are less.
Preferably, in the step (2), the base is potassium carbonate powder.
The potassium carbonate powder is used as a catalyst, the solubility of the potassium carbonate powder in an organic solvent is low, and most of the potassium carbonate can be removed by filtering after the reaction is finished, so that the separation and purification steps of the product can be simplified, and the production efficiency is improved.
Preferably, in step (2), the primary purification process comprises the following steps: filtering, neutralizing the filtrate, filtering again, and concentrating.
Further, in the step (2), the primary purification process comprises the following steps: filtering, neutralizing the filtrate until the pH is 7-8, filtering again, and concentrating.
Preferably, in the step (2), the particle size of the potassium carbonate powder is less than 100 μm; the molar ratio of the compound of formula II in step (1) to the potassium carbonate powder in step (2) is 1:1.5 to 4.
When the amount of the potassium carbonate powder is too large, the difficulty in removing the potassium carbonate powder after the reaction is completed (for example, the pore is easily blocked during filtration) is increased, the three wastes are increased, and the production cost is increased. The invention can make the potassium carbonate powder have larger specific surface area and improve the catalytic efficiency by controlling the grain diameter of the potassium carbonate powder to be less than 100 mu m, thereby reducing the dosage of the potassium carbonate powder under the condition of ensuring the yield.
As a further preference, in the step (2), the particle size of the potassium carbonate powder is less than 100 μm; the molar ratio of the compound of formula II in step (1) to the potassium carbonate powder in step (2) is 1:1.5 to 2.
Preferably, the mass to volume ratio of the compound of formula II in step (1) to the acetonitrile in step (2) is 1kg:6 to 10L.
As a further preference, the mass to volume ratio of the compound of formula II in step (1) to the acetonitrile in step (2) is 1kg:6 to 8L.
Preferably, in the step (2), the temperature of the hot beating is 70-75 ℃ during the hot beating process by adding the acetonitrile.
Preferably, in step (1), the organic solvent is methanol, and the acid is a hydrogen chloride methanol solution.
Further, the content of hydrogen chloride in the hydrogen chloride methanol solution is 3-5 mol/L; the mass volume ratio of the compound shown in the formula II to the hydrogen chloride methanol solution is 1kg:1 to 2L.
Preferably, in the step (2), the temperature of the ring-closing reaction is 0 to 35 ℃.
More preferably, in the step (2), the temperature of the ring-closing reaction is 20 to 30 ℃.
Preferably, in the step (1), the temperature of the tert-butoxycarbonyl removal reaction is 20-30 ℃ and the time is 10-18 h.
Compared with the prior art, the invention has the following advantages:
(1) The invention adopts a 'one-pot' continuous reaction and is matched with a special product purification method, so that the prepared suvorexant has higher purity while shortening the preparation flow, simplifying the process steps and improving the production efficiency;
(2) The invention adopts potassium carbonate powder as the catalyst of the ring closing reaction, which can simplify the separation and purification steps of the product; and, by controlling the particle size of the potassium carbonate powder, the formation of potassium chloride during the primary purification can be reduced.
Detailed Description
The present invention will be further described with reference to the following examples.
General examples
A preparation method of a Su Wo Leisheng intermediate comprises the following steps:
(1) Mixing a compound of a formula II, an organic solvent and acid, and then carrying out a tert-butyloxycarbonyl removal reaction at 20-30 ℃ for 10-18 h to obtain a mixed solution containing a compound of a formula III; the reaction route is as follows:
(2) Mixing a mixed solution containing a compound of a formula III with potassium carbonate powder with the particle size of less than 100 mu m, wherein the molar ratio of the compound of the formula II in the step (1) to the potassium carbonate powder in the step (2) is 1: 1.5-4, carrying out ring closing reaction at 0-35 ℃; and (3) after full reaction, filtering, neutralizing the filtrate, filtering again, concentrating, adding acetonitrile, and carrying out thermal pulping at 70-75 ℃, wherein the mass volume ratio of the compound of the formula II in the step (1) to the acetonitrile in the step (2) is 1kg:6 to 10L, filtering the mixture while the mixture is hot, concentrating the mixture, adding ethyl acetate into the mixture to carry out hot pulping, and filtering the mixture to obtain a compound shown as a formula I, namely a Suvorexant intermediate; the reaction route is as follows:
as a specific embodiment, in step (1), the organic solvent is methanol, the acid is a hydrogen chloride methanol solution (wherein the content of hydrogen chloride is 3 to 5 mol/L), and the mass-to-volume ratio of the compound of formula II to the hydrogen chloride methanol solution is 1kg: 1-2L; in the step (2), the filtrate is neutralized by adding a hydrogen chloride methanol solution.
Example 1
Preparing a suvorexant intermediate by:
(1) Synthesis of a compound of formula III:
adding 1.8kg of a compound shown in the formula II and 6.2L of methanol into a 10L reaction kettle, heating to 30 ℃, stirring and dissolving, then dropwise adding 2.5L4mol/L hydrogen chloride methanol solution, and carrying out heat preservation reaction at 30 ℃ for 16h to obtain mixed solution containing a compound shown in the formula III;
(2) Synthesis of compounds of formula I:
adding 1.2kg of potassium carbonate powder with the particle size of D90=45 μm into the mixed solution containing the compound of the formula III, and carrying out heat preservation reaction at 30 ℃ for 8h to obtain a mixed solution containing the compound of the formula I;
(3) Isolation and purification of the compound of formula I:
filtering the mixed solution containing the compound of the formula I, adjusting the pH of the filtrate to 7.5 +/-0.5 by using 4mol/L hydrogen chloride methanol solution, filtering once again, concentrating the filtrate to oily matter, adding 12.6L acetonitrile, heating to 70 ℃, pulping for 1h, filtering, concentrating the filtrate to oily matter, adding 3.6L ethyl acetate, heating to 50 ℃, stirring for 1h, and filtering to obtain 897g (the theoretical yield is 1.147 kg) of an off-white solid compound of the formula I, namely a suvorexant intermediate.
In this example, the purity of the compound of formula I was found to be 98.05% and the yield of the compound of formula I from the compound of formula III was found to be 78.2%.
Example 2
Preparing a suvorexant intermediate by:
(1) Synthesis of a compound of formula III:
adding 1.8kg of a compound shown in the formula II and 6.2L of methanol into a 10L reaction kettle, heating to 30 ℃, stirring and dissolving, then dropwise adding 2.5L4mol/L hydrogen chloride methanol solution, and carrying out heat preservation reaction at 30 ℃ for 16h to obtain mixed solution containing a compound shown in the formula III;
(2) Synthesis of compounds of formula I:
adding 1.4kg of potassium carbonate powder with the particle size of D90=45 μm into the mixed solution containing the compound of the formula III, and carrying out heat preservation reaction at 30 ℃ for 8h to obtain a mixed solution containing the compound of the formula I;
(3) Isolation and purification of the compound of formula I:
filtering the mixed solution containing the compound of the formula I, adjusting the pH of the filtrate to 7.5 +/-0.5 by using 4mol/L hydrogen chloride methanol solution, filtering once again, concentrating the filtrate to oily matter, adding 15L of acetonitrile, heating to 70 ℃, pulping for 1h, filtering, concentrating the filtrate to oily matter, adding 3.6L of ethyl acetate, heating to 50 ℃, stirring for 1h, filtering, and obtaining 845g (the theoretical yield is 1.147 kg) of an off-white solid compound of the formula I, namely a suvorexant intermediate.
In this example, the purity of the compound of formula I was determined to be 98.55% and the yield of the compound of formula I from the compound of formula III was determined to be 73.7%.
Comparative example 1
Preparing a suvorexant intermediate by:
(1) Synthesis of a compound of formula III:
adding 18g of the compound shown in the formula II and 62mL of methanol into a reaction bottle, heating to 30 ℃, stirring and dissolving, then dropwise adding 25mL of a 4mol/L hydrogen chloride methanol solution, and carrying out heat preservation reaction at 30 ℃ for 16h to obtain a mixed solution containing the compound shown in the formula III;
(2) Isolation and purification of the compound of formula III:
the mixture containing the compound of formula III was concentrated to a dry oil, 12mL of saturated sodium carbonate solution was added, extraction was performed with a mixture of dichloromethane and ethanol (18 mL × 2) in a volume ratio of 2:1, the organic phases were combined, dried over anhydrous magnesium sulfate, concentrated to an oil, added with ethyl acetate 60ml, stirred at 20 ℃ for 2h, filtered, and dried to obtain 9.8g (theoretical yield 13.1 g) of the compound of formula III in 74.8% yield and 98.4% purity.
(3) Isolation and purification of the compound of formula I:
adding the compound shown in the formula III into 60mL of methanol, heating to 30 ℃, stirring and dissolving, adding 14g of potassium carbonate powder with the particle size of D90=45 μm, and carrying out heat preservation reaction at 30 ℃ for 8h to obtain a mixed solution containing the compound shown in the formula I;
(4) Isolation and purification of the compound of formula I:
filtering the mixed solution containing the compound of the formula I, adjusting the pH of the filtrate to 7.5 +/-0.5 by using 4mol/L hydrogen chloride methanol solution, filtering once again, concentrating the filtrate to oily matter, adding 150mL of acetonitrile, heating to 70 ℃, pulping for 1h, filtering, concentrating the filtrate to oily matter, adding 360mL of ethyl acetate, heating to 50 ℃, stirring for 1h, and filtering to obtain 7.3g (theoretical yield is 8.6 g) of an off-white solid compound of the formula I, namely a suvorexant intermediate, wherein the yield is 84.9%.
In this example, the purity of the compound of formula I was determined to be 98.32% and the overall yield of the compound of formula I from the compound of formula III was determined to be 63.6%.
Comparing example 1 with comparative example 1, it can be seen that: the compound of formula I obtained in example 1 has a purity comparable to that of comparative example 1, and a yield significantly higher than that of comparative example 1. It is demonstrated that the yield of the compound of formula I can be increased by using a "one-pot" continuous reaction compared to a non "one-pot" method (i.e. synthesizing the compound of formula I by separation and purification after synthesizing the compound of formula III). This is due to: the one-pot method can avoid the loss of the compound shown in the formula III in the separation and purification process, thereby improving the yield of the finally prepared compound shown in the formula I.
Comparative example 2
Preparing a suvorexant intermediate by:
(1) Synthesis of a compound of formula III:
adding 18g of the compound shown in the formula II and 62mL of methanol into a reaction bottle, heating to 30 ℃, stirring and dissolving, then dropwise adding 25mL of a 4mol/L hydrogen chloride methanol solution, and carrying out heat preservation reaction at 30 ℃ for 16h to obtain a mixed solution containing the compound shown in the formula III;
(2) Synthesis of compounds of formula I:
adding 14g of potassium carbonate powder with the particle size of D90=45 μm into the mixed solution containing the compound of the formula III, and continuing to perform heat preservation reaction at 30 ℃ for 8h to obtain a mixed solution containing the compound of the formula I;
(3) Isolation and purification of the compound of formula I:
the mixture containing the compound of formula I was filtered, the pH of the filtrate was adjusted to 7.5 ± 0.5 with 4mol/L methanolic hydrogen chloride solution, filtered once more, the filtrate was concentrated to dryness, 12mL of saturated sodium carbonate solution was added, extraction was performed with a mixture of dichloromethane and ethanol (18 mL × 3) in a volume ratio of 2:1, the organic phases were combined, dried over anhydrous magnesium sulfate, and the solvent was removed by rotary evaporation to obtain 7.8g (theoretical yield 11.47 g) of an off-white solid compound of formula I, i.e. suvorexant intermediate.
In this example, the purity of the compound of formula I was found to be 97.89% and the yield of the compound of formula I from the compound of formula III was found to be 68%.
Comparing example 2, comparative example 1 and comparative example 2, it can be seen that: the compound of formula I obtained in example 2 has a purity slightly higher than that of comparative example 2, and is equivalent to that of comparative example 1; the yield of example 2 is significantly higher than that of comparative example 2. It is demonstrated that the method of example 2 can effectively remove the by-products generated by the continuous reaction in one-pot process, and the purity of the final compound of formula I can reach the level equivalent to that of the non-one-pot process (i.e. the compound of formula I is synthesized after the compound of formula III is synthesized by separation and purification), and the yield is higher. In addition, the mixed solution of dichloromethane and ethanol in comparative example 2 can hardly be recovered, and three wastes are too high. This is due to: when a one-pot method is adopted for continuous reaction, a small amount of raw materials (the compound of the formula II) can not be completely reacted after the tert-butyloxycarbonyl removal reaction in the step (1), ester hydrolysis can occur under the action of alkali after the contact with alkali in the step (2), byproducts are formed, the byproducts are difficult to remove by a method of extracting a mixed solution of dichloromethane and ethanol, the finally prepared compound of the formula I has low purity, and the dichloromethane and ethanol mixed solution is difficult to layer during extraction, so that the compound of the formula I has high loss and low yield; and the purification method of acetonitrile hot beating is adopted, so that the by-product generated by the hydrolysis of the compound ester shown in the formula II can be effectively removed, and the loss of the compound shown in the formula I in the purification process is less.
The raw materials and equipment used in the invention are common raw materials and equipment in the field if not specified; the methods used in the present invention are conventional in the art unless otherwise specified.
The above description is only a preferred embodiment of the present invention, and is not intended to limit the present invention, and all simple modifications, alterations and equivalents of the above embodiments according to the technical spirit of the present invention are still within the protection scope of the technical solution of the present invention.
Claims (10)
1. A preparation method of a Su Wo Leisheng intermediate is characterized by comprising the following steps:
(1) Mixing a compound of a formula II, an organic solvent and an acid, and then carrying out a tert-butyloxycarbonyl removal reaction to obtain a mixed liquid containing a compound of a formula III; the reaction route is as follows:
(2) Mixing the mixed solution containing the compound of the formula III with alkali, performing ring closing reaction, performing primary purification to remove the alkali, adding acetonitrile, performing hot pulping, filtering while the mixture is hot, concentrating, adding ethyl acetate, performing hot pulping, and filtering to obtain a compound of the formula I, namely a Suvorexant intermediate; the reaction route is as follows:
2. the method according to claim 1, wherein in the step (2), the base is potassium carbonate powder.
3. The method according to claim 2, wherein in the step (2), the preliminary purification process comprises the steps of: filtering, neutralizing the filtrate, filtering again, and concentrating.
4. The method according to claim 2, wherein in the step (2), the potassium carbonate powder has a particle size of less than 100 μm; the molar ratio of the compound of formula II in step (1) to the potassium carbonate powder in step (2) is 1:1.5 to 4.
5. The process according to claim 1, wherein the mass to volume ratio of the compound of formula II in step (1) to the acetonitrile in step (2) is 1kg:6 to 10L.
6. The method according to claim 1, wherein in the step (2), the temperature of the hot beating is 70-75 ℃ during the hot beating by adding acetonitrile.
7. The method according to claim 1, wherein in the step (1), the organic solvent is methanol, and the acid is a methanolic solution of hydrogen chloride.
8. The method according to claim 7, wherein the hydrogen chloride-methanol solution contains 3 to 5mol/L of hydrogen chloride; the mass volume ratio of the compound shown in the formula II to the hydrogen chloride methanol solution is 1kg:1 to 2L.
9. The method according to claim 1, wherein the temperature of the ring-closing reaction in the step (2) is 0 to 35 ℃.
10. The method according to claim 1, wherein the t-butoxycarbonyl removing reaction in step (1) is carried out at a temperature of 20 to 30 ℃ for 10 to 18 hours.
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| US20120208815A1 (en) * | 2007-03-01 | 2012-08-16 | Matthew Burger | Pim kinase inhibitors and methods of their use |
| CN103923068A (en) * | 2014-02-13 | 2014-07-16 | 武汉珈瑜科技有限公司 | Compound for preparing suvorexant and preparation method thereof |
| CN108084145A (en) * | 2017-12-12 | 2018-05-29 | 南通常佑药业科技有限公司 | Ticagrelor midbody and preparation method thereof |
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| US20120208815A1 (en) * | 2007-03-01 | 2012-08-16 | Matthew Burger | Pim kinase inhibitors and methods of their use |
| CN103923068A (en) * | 2014-02-13 | 2014-07-16 | 武汉珈瑜科技有限公司 | Compound for preparing suvorexant and preparation method thereof |
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