CN103274968B - Method for producing amantadine compound - Google Patents
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- CN103274968B CN103274968B CN201310222291.4A CN201310222291A CN103274968B CN 103274968 B CN103274968 B CN 103274968B CN 201310222291 A CN201310222291 A CN 201310222291A CN 103274968 B CN103274968 B CN 103274968B
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Abstract
The invention provides a method for producing an anantadine compound. The method comprises a first step of carrying out an oxidation reaction on 1- adamantylmethanol to obtain adamantylcarboxaldehyde (A1); a second step of synthesizing an intermediate (A2) by using adamantylcarboxaldehyde (A1) as a raw material; and a third step of synthesizing the amantadine compound (I) by using the intermediate (A2) as a raw material. The invention also provides a method for producing saxagliptin. The production methods provided by the invention are reasonable in process, simple in operation and friendly to environment. The whole reaction process is mild in conditions and has no rigorous anhydrous free-oxygen reaction. Both yield and purity are increased greatly.
Description
Technical Field
The invention relates to a method for producing a compound, in particular to a method for producing amantadine (N-tert-butyloxycarbonyl-3-hydroxy-1-adamantyl-D-glycine, CAS: 361442-00-4) shown in a structural formula (I) in the specification.
Background
Saxagliptin (saxagliptin) is a novel dipeptidyl peptidase-IV (DPP-IV, endogenous secretin) inhibitor developed by schnobel corporation in combination with astrazepam. It can increase the level of endogenous glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) by selectively inhibiting DPP-4, thereby regulating blood sugar. FDA approval of saxagliptin for the treatment of hyperglycemia in adult type 2 diabetic patients at 3 months 2010; in 5 months 2011, official approval of SFDA was obtained in china. The medicine can be used for single-drug treatment and can also be combined with metformin treatment on the basis of poor control of metformin. Clinical studies have confirmed that saxagliptin has the advantages of outstanding therapeutic effects, long-lasting effects, and the like. The chemical structure of saxagliptin is as follows:
methods for synthesizing saxagliptin have been reported, for example, patent documents WO2011117393A, WO2010032129A, US20060035954, US 2005090539; and documents j.med.chem, 2005, 48: 5025-: 1169-1176. The preparation and production of saxagliptin is mostly achieved by amidation reaction using an adamantane compound (I) and a tetrahydropyrrole amide compound (II), and the synthetic route is as follows:
from the synthetic method of saxagliptin, the compounds I and II are important intermediates for successfully synthesizing saxagliptin. The synthesis of the adamantane compound I mainly adopts enzyme catalytic ammoniation reduction to construct a chiral center (reference WO 2010032129A; US 2005090539; adv. Syn. Cat., 2007, 349: 1369-. The synthetic route is as follows:
although the enzymatic ammonification reduction method has the advantages of high conversion rate (about 99%) and good selectivity (ee > 99%), the biological enzyme technology is not mature, and the biological enzyme is difficult to control from the synthetic chemistry perspective.
There is also literature on the synthesis of compound (I) using chemical resolution (see j.med. chem, 2005, 48: 5025; WO 2011117393; US 2005090539). Document j.med.chem, 2005, 48: 5025 the published synthetic route is as follows:
this method also enables the synthesis of compound (I), but the greatest disadvantage of this method is that the oxidation conditions of the last step are severe and large amounts of dihydroxy and trihydroxy impurities are produced. Thus, the separation and purification of compound I are extremely difficult, and a column separation is required to obtain a high-purity product. This results in very low yields of compound (I) and very high preparation costs, which are not suitable for large scale up production.
Disclosure of Invention
In order to overcome the problem that the method for synthesizing the amantadine compound in the prior art is difficult to produce on a large scale, the application provides a novel synthesis and production method so as to overcome the defects of the existing chemical resolution method.
In a first aspect of the present invention, there is provided a process for producing an amantadine compound (N-tert-butoxycarbonyl-3-hydroxy-1-adamantyl-D-glycine, CAS: 361442-00-4) having the following structure:
the method according to the first aspect of the present invention comprises the steps of:
step 1, carrying out oxidation reaction on 1-adamantane methanol to obtain adamantane formaldehyde (A1);
step 2, synthesizing an intermediate (A2) by taking adamantane formaldehyde as a raw material;
and 3, synthesizing the amantadine compound (I) by taking the intermediate (A2) as a raw material.
Wherein the adamantane formaldehyde (A1) has the following structural formula:
wherein the structural formula of the intermediate (A2) is as follows:
in a first preferred embodiment of the first aspect of the present invention, in step 1, the oxidation reaction of 1-adamantanemethanol is preferably a Tempo oxidation reaction, comprising the steps of: reacting with hypochlorite in the presence of bicarbonate, 2,6, 6-tetramethylpiperidinyloxy free radical and alkali metal bromide.
In a first preferred embodiment of said first aspect, the reaction temperature in step 1 is preferably in the range of-20 to 30 ℃, preferably in the range of-10 ℃ to 10 ℃, more preferably in the range of-5 ℃ to 10 ℃, more preferably in the range of 0 ℃ to 10 ℃, more preferably in the range of 5 ℃ to 10 ℃.
In a first preferred embodiment of said first aspect, the termination time of the reaction of step 1 can be judged by a person skilled in the art by means of the prior art, and the present invention is preferably 10-60min, more preferably 15-50min, more preferably 20-40min, such as 25min, 30min, etc.
Wherein, the bicarbonate in the step 1 is preferably any one or more of alkali metal bicarbonate, such as potassium bicarbonate, sodium bicarbonate or a mixture of the potassium bicarbonate and the sodium bicarbonate, and more preferably sodium bicarbonate.
Among them, the alkali metal bromide in step 1 is preferably sodium bromide, potassium bromide, or a mixture of the two, and more preferably sodium bromide.
Wherein, the hypochlorite in step 1 is preferably an alkali metal hypochlorite, such as potassium hypochlorite, sodium hypochlorite or a mixture of the two, and more preferably sodium hypochlorite.
In a preferred embodiment of the first aspect of the present invention, in step 1, the order of addition is as follows: 1-adamantane methanol, bicarbonate, 2,6, 6-tetramethyl piperidyl oxygen free radical and alkali metal bromide are added into a solvent, and then hypochlorite is added.
It should be understood that the various solid compounds described in step 1 may be added in the form of a solution, or in the form of a solid, and the present invention is not limited thereto.
In a first preferred embodiment of said first aspect, the temperature of the reaction system during the addition of hypochlorite is preferably controlled in the range of-20 to 30 ℃, more preferably in the range of-10 ℃ to 10 ℃, more preferably in the range of-5 ℃ to 10 ℃, more preferably in the range of 0 ℃ to 10 ℃, more preferably in the range of 5 ℃ to 10 ℃.
In a first preferred embodiment of the first aspect, the solvent in step 1 may be any one or more of water and an organic solvent, such as a mixture of water and dichloromethane.
In a first preferred embodiment of the first aspect, the reaction product in step 1 is preferably collected by: the organic layer was collected and washed with saturated aqueous sodium sulfite solution to remove the solvent.
More preferably, the temperature during said removal of the solvent is preferably not more than 50 ℃, more preferably not more than 45 ℃.
In a second preferred embodiment of the first aspect of the invention, step 2 can be prepared in a manner disclosed in the prior art, as described in document j.med.chem, 2005, 48: 5025.
In a third preferred embodiment of the first aspect of the invention, step 3 can be prepared in a manner disclosed in the prior art, as disclosed in document j.med.chem, 2005, 48: 5025. Preferably, however, the step 3 reaction step comprises:
step 3.1, adding nitric acid and an intermediate (A2) into concentrated sulfuric acid for reaction;
step 3.2, adjusting the pH value of the reaction liquid obtained in the step 3.1 to be 14 or higher under alkaline conditions, adding di-tert-butyl dicarbonate (BOC anhydride), and adjusting the pH value to 3-4; continuing the reaction;
and 3.3, separating and synthesizing a product after the reaction is finished to obtain the amantadine compound (I).
In a third preferred embodiment of the first aspect of the present invention, the concentrated sulfuric acid in step 3.1 of the present invention is preferably sulfuric acid with a mass concentration of 90% or more, preferably 95% or more, and most preferably 98% sulfuric acid.
In a third preferred embodiment of the first aspect of the present invention, the nitric acid in step 3.1 of the present invention is preferably at a concentration of 3 to 20mol/L, more preferably 5 to 15mg/L, more preferably 8 to 13mol/L, such as 10mol/L, 12 mol/L.
In a third preferred embodiment of the first aspect of the present invention, the reaction temperature in step 3.1 of the present invention is preferably from 15 to 40 ℃, more preferably from 20 to 35 ℃, more preferably from 25 to 30 ℃, and may be, for example, at room temperature.
In a third preferred embodiment of the first aspect of the invention, the step 3.1 feeding method is preferably: adding nitric acid into concentrated sulfuric acid, and controlling the temperature to be not more than 40 ℃, preferably not more than 35 ℃, and more preferably not more than 30 ℃; intermediate a2 was then added.
In a third preferred embodiment of the first aspect of the present invention, the reaction termination time in step 3.1 can be judged by a person skilled in the art by the prior art, and the preferred reaction time in step 3.1 of the present invention is 12-36h, more preferably 15-24h, such as 18h, 20h, etc.
In a third preferred embodiment of the first aspect of the present invention, in the step 3.2 of adjusting the pH to alkaline, preferably any one or more of sodium hydroxide, potassium hydroxide or ammonia water is used, and more preferably sodium hydroxide is used.
In the third preferred embodiment of the first aspect of the present invention, in the step 3.2 of adjusting the pH value to 3-4, it is preferable to use any one or a mixture of hydrochloric acid, sulfuric acid and nitric acid, and it is preferable to use hydrochloric acid.
In a third preferred embodiment of the first aspect of the present invention, the reaction termination time in step 3.2 can be judged by one skilled in the art by the prior art, and the preferred reaction time in step 3.2 of the present invention is 12-36h, more preferably 15-24h, such as 18h, 20h, etc.
In a third preferred embodiment of the first aspect of the present invention, in step 3.3, the reaction product is preferably collected by: and collecting an organic layer of the system after the reaction is finished, and recrystallizing to obtain the amantadine compound (I).
In a third preferred embodiment of the first aspect, in step 3.3, the recrystallization solvent is preferably acetonitrile.
In a fourth preferred embodiment of the first aspect of the invention, the step 3 method of operation is most preferably:
step 3.1, adding nitric acid and an intermediate (A2) into concentrated sulfuric acid for reaction;
step 3.2, pouring the reaction liquid obtained in the step 3.1 into water, adjusting the pH value to be 14 or higher under alkaline conditions, adding di-tert-butyl dicarbonate (BOC anhydride), and adjusting the pH value to 3-4; adding an organic solvent for continuous reaction;
and 3.3, separating and synthesizing a product after the reaction is finished to obtain the amantadine compound (I).
In a fourth preferred embodiment of said first aspect, the organic solvent is preferably a water-immiscible solvent, such as ethyl acetate, butyl acetate, etc., preferably ethyl acetate.
In a second aspect, the invention provides a method for producing saxagliptin, comprising the steps of:
step 1, synthesizing amantadine (I) by any of the methods described in the first aspect of the present invention;
and 2, reacting the amantadine (I) with the tetrahydropyrrole amide compound (II) to obtain the saxagliptin.
It should be understood that:
in any of the above-mentioned methods of the present invention, the molar ratio between the reactants may be selected by those skilled in the art according to the desired reaction conditions, or may be in excess of a certain molar ratio of the reactants in order to accelerate the reaction. In any of the above processes of the invention, the amount of catalyst used may be selected by one skilled in the art as a catalytic amount.
Any of the synthetic methods described in the first aspect of the invention, as well as the various preferred embodiments, may be applied to the second aspect of the invention without limitation.
The various aspects of the invention described above, as well as the various preferred embodiments, can be combined arbitrarily by a person skilled in the art without restriction.
The invention takes 1-adamantane methanol as raw material, and the synthesis of the amantadine compound (I) is realized through 6 steps of reaction including oxidation, butt joint, hydrolysis, hydrogenation, hydroxylation and amino protection. The first step of oxidation reaction improves Swern oxidation used in the previous project into innovative 2,2,6, 6-tetramethyl piperidyl oxygen free radical (Tempo) oxidation, so that the step of reaction overcomes the harsh reaction conditions of low-temperature deep cooling, no water and no oxygen, and the yield and the purity of the product are greatly improved.
The method adopts an innovative oxidation method from the compound A2 to the compound (I), and can integrate the last 2 steps by a one-pot method, thereby having great breakthrough in yield and purity.
The production method provided by the invention has the advantages of reasonable process, simple operation and environmental friendliness; the whole reaction process has mild conditions and no harsh anhydrous and anaerobic reaction.
The process provided by the present aspect successfully synthesizes an adamantane compound (I) having a high optical activity in a large amount with an extremely high yield, ee > 99%.
Drawings
FIG. 1 is a schematic synthesis scheme for the production of amantadine according to a first preferred embodiment of the present invention;
FIG. 2 is a synthesis scheme for the production of amantadine according to a second preferred embodiment of the present invention.
Detailed Description
The process for producing an amantadine compound (I) according to the present invention will be described in detail with reference to fig. 1 and examples.
Example 1
Step 1
According to document j.med.chem, 2005, 48: 5025, 1-adamantane methanol oxidation reaction to give adamantanecarboxaldehyde (A1).
Step 2
According to document j.med.chem, 2005, 48: 5025, the intermediate (A2) is obtained by docking adamantane formaldehyde (A1) with 2-amino-2-phenyl ethanol (CAS: 7568-92-5, DL-phenylglycinol), hydrolyzing, and hydrogenating.
Step 3
Adding 98wt% sulfuric acid (12.5L) into a 30L reaction kettle, cooling to 10 ℃, dropwise adding 10N nitric acid (1.8L), wherein the internal temperature is not more than 30 ℃ in the dropwise adding process; adamantane intermediate A2 (2.5 kg)) was added to the reaction solution in portions for 1 hour; stirred at room temperature for 18 h.
Pouring the reaction solution into 125L of water, and adjusting the pH value of the reaction solution to 14 by using 50% sodium hydroxide solution; BOC anhydride (11 Kg) was added and stirred at room temperature for 18 hours, the pH was adjusted to 3-4 with 1N hydrochloric acid, 75L ethyl acetate was added and stirred for 30 min.
Standing; the lower layer was discarded and the organic layer was concentrated in a 55 ℃ water bath; acetonitrile is added into the concentrate for recrystallization to obtain 2.0Kg of the adamantane intermediate (I), the yield is 80 percent, and ee is more than 99 percent.
Example 2
Step 1
1-adamantane methanol (250 g, 1.5mol, CAS: 770-71-8), dichloromethane (1.25L), sodium bicarbonate (63.25 g, 0.75 mol), water (380 g), 2,2,6, 6-tetramethylpiperidinyloxy free radical (Tempo, catalytic amount, such as 2.5g, CAS: 2564-83-2), sodium bromide (31 g, 0.3 mol) are put into a 5L four-mouth bottle, stirring is started, and the internal temperature of the system is reduced to 0 +/-5 ℃ by a salt-freezing bath; dropwise adding sodium hypochlorite solution (10 wt%, 1.8 kg), and keeping the temperature of the system not more than 10 ℃ in the dropwise adding process; stirring for 0.5h while keeping the temperature, standing, separating out the lower layer, and discarding the upper layer: adding saturated sodium sulfite solution 1L into the lower layer, stirring for 15min, standing, and discarding the upper layer; the lower layer was collected and concentrated under reduced pressure, and the temperature of the water bath was not higher than 45 ℃ to obtain 237.5g of adamantanecarboxaldehyde (A1) as a yellow oil with a yield of 95%.
Step 2
According to document j.med.chem, 2005, 48: 5025, the intermediate (A2) is obtained by docking adamantane formaldehyde (A1) with 2-amino-2-phenyl ethanol (CAS: 7568-92-5, DL-phenylglycinol), hydrolyzing, and hydrogenating.
Step 3
Adding 98wt% sulfuric acid (12.5L) into a 30L reaction kettle, cooling to 10 ℃, dropwise adding 10N nitric acid (1.8L), wherein the internal temperature is not more than 30 ℃ in the dropwise adding process; adamantane intermediate A2 (2.5 kg)) was added to the reaction solution in portions for 1 hour; stirred at room temperature for 18 h.
Pouring the reaction solution into 125L of water, and adjusting the pH value of the reaction solution to 14 by using 50% sodium hydroxide solution; BOC anhydride (11 Kg) was added and stirred at room temperature for 18 hours, the pH was adjusted to 3-4 with 1N hydrochloric acid, 75L ethyl acetate was added and stirred for 30 min.
Standing; the lower layer was discarded and the organic layer was concentrated in a 55 ℃ water bath; acetonitrile is added into the concentrate for recrystallization to obtain 2.0Kg of the adamantane intermediate (I), the yield is 80 percent, and ee is more than 99 percent.
Example 3
The amantadine compound (I) prepared in example 1 or 2 was reacted with a tetrahydropyrrolamide compound (II) ((1S, 3S,5S) -2-azabicyclo [3.1.0] hexane-3-carboxamide, CAS: 361440-68-8) according to the prior art (see references WO2011117393A, WO2010032129A, US20060035954, US2005090539, and J.Med.Chem, 2005, 48: 5025-.
The embodiments of the present invention have been described in detail, but the embodiments are merely examples, and the present invention is not limited to the embodiments described above. Any equivalent modifications and substitutions to those skilled in the art are also within the scope of the present invention. Accordingly, equivalent changes and modifications made without departing from the spirit and scope of the present invention should be covered by the present invention.
Claims (9)
1. A method of producing an amantadine compound having the structure:
the method is characterized by comprising the following steps:
step 1, carrying out oxidation reaction on 1-adamantane methanol to obtain adamantane formaldehyde (A1);
step 2, synthesizing an intermediate (A2) by taking adamantane formaldehyde as a raw material;
step 3, synthesizing an amantadine compound (I) by taking the intermediate (A2) as a raw material;
wherein the adamantane formaldehyde (A1) has the following structural formula:
wherein the structural formula of the intermediate (A2) is as follows:
wherein,
in the step 1, the oxidation reaction of the 1-adamantane methanol is a Tempo oxidation reaction, and the steps comprise: reacting with hypochlorite in the presence of bicarbonate, 2,6, 6-tetramethylpiperidinyloxy free radical and alkali metal bromide;
step 3 the reaction steps comprise:
step 3.1, adding nitric acid and an intermediate (A2) into concentrated sulfuric acid for reaction;
step 3.2, adjusting the pH value of the reaction solution obtained in the step 3.1 to be 14 or higher under alkaline conditions, adding di-tert-butyl dicarbonate, and adjusting the pH value to 3-4; continuing the reaction;
and 3.3, separating and synthesizing a product after the reaction is finished to obtain the amantadine compound (I).
2. The process according to claim 1, wherein the reaction temperature in step 3.1 is 15-40 ℃.
3. The method of claim 1, wherein the step 3.1 feeding method comprises the following steps: adding nitric acid into concentrated sulfuric acid, and controlling the temperature not to exceed 40 ℃; intermediate (a2) was then added.
4. The process according to claim 1, wherein the reaction time of step 3.1 or step 3.2 is 10 to 36 h.
5. The method according to claim 1, wherein in step 3.3, the reaction product is collected by: and collecting an organic layer of the system after the reaction is finished, and recrystallizing to obtain the amantadine compound (I).
6. The process according to claim 5, characterized in that the recrystallization solvent is acetonitrile.
7. The process according to claim 1, wherein the reaction temperature in step 1 is in the range of-20 ℃ to 30 ℃.
8. The method according to claim 1, wherein the reaction time in step 1 is 10-60 min.
9. A method of producing saxagliptin, comprising the steps of:
step 1, synthesizing amantadine (I) by the method of claim 1;
step 2, reacting amantadine (I) with tetrahydropyrrole amide compound (II) to obtain saxagliptin; wherein the structural formula of the pyrrolidine amide compound (II) is shown as follows:
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103435536A (en) * | 2013-09-09 | 2013-12-11 | 嘉兴学院 | Pyrrole derivative of S-proline having cyclopropane structure and preparation method of pyrrole derivative |
| CN103467361A (en) * | 2013-09-09 | 2013-12-25 | 嘉兴学院 | Morpholine derivative with S-proline in cyclopropane structure and preparation method thereof |
| CN103467360A (en) * | 2013-09-09 | 2013-12-25 | 嘉兴学院 | Morpholine derivative with R-proline in cyclopropane structure and preparation method thereof |
| CN103922907B (en) * | 2014-04-15 | 2015-11-04 | 浙江师范大学 | A kind of preparation method of adamantane formaldehyde |
| CN104098487A (en) * | 2014-07-31 | 2014-10-15 | 天津民祥生物医药科技有限公司 | Method for preparing N-tert-butyloxycarbonyl-3-hydroxy-1-adamantyl-d-glycine |
| CN104326944A (en) * | 2014-11-04 | 2015-02-04 | 崇州合瑞科技有限公司 | Method for preparing Boc-L-threonine |
| CN113666846B (en) * | 2021-08-31 | 2023-06-27 | 济南立德医药技术有限公司 | Synthesis method of saxagliptin intermediate |
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| WO2006020664A2 (en) * | 2004-08-11 | 2006-02-23 | Bristol-Myers Squibb Company | Ammonolysis process for the preparation of intermediates for dpp iv inhibitors |
| CN101898958A (en) * | 2010-07-16 | 2010-12-01 | 广东工业大学 | A kind of preparation method of 1,3-adamantane dicarboxylic acid |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2006020664A2 (en) * | 2004-08-11 | 2006-02-23 | Bristol-Myers Squibb Company | Ammonolysis process for the preparation of intermediates for dpp iv inhibitors |
| CN101898958A (en) * | 2010-07-16 | 2010-12-01 | 广东工业大学 | A kind of preparation method of 1,3-adamantane dicarboxylic acid |
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