CN103274968B - Method for producing amantadine compound - Google Patents
Method for producing amantadine compound Download PDFInfo
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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 present invention relates to a kind of production method of compound, particularly relate to a kind of method of producing amantadine (N-tertbutyloxycarbonyl-3-hydroxyl-1-adamantyl-D-glycine, CAS:361442-00-4) shown in structural formula (I) in ensuing disclosure.
Background technology
A kind of novel dipeptidyl peptidase-IV (DPP-IV, the endogenous secretin) inhibitor that BMS-477118 (saxagliptin) Shi Shiguibao company and Astrazeneca AB develop jointly.It is by Selective depression DPP-4, can raise endogenous glucagon-like-peptide-1 (GLP-1) and glucose dependency pancreotropic hormone release polypeptide (GIP) level, thus regulate blood sugar.In March, 2010 U.S. FDA approval BMS-477118 is used for the treatment of the hyperglycemia of adults with type 2 diabetes; In May, 2011, obtain SFDA official approval in China.This medicine can single therapy and also can control Or Metformin In Treating is combined on not good basis at N1,N1-Dimethylbiguanide.Clinical study has confirmed that BMS-477118 has curative effect and gives prominence to, the advantages such as persistent.BMS-477118 chemical structure is as follows:
Synthetic method about BMS-477118 has been reported, as patent documentation WO2011117393A, WO2010032129A, US20060035954, US2005090539; And document J.Med.Chem, 2005,48:5025-5037 and Org.Process.Res.Dev, 2009,13:1169-1176.Prior art is most by utilizing the amidate action of adamantane compound (I) and Pyrrolidine amide compound (II) to realize the preparation of BMS-477118 and production, and synthetic route is as follows:
From the synthetic method of BMS-477118, Compound I and II are the important intermediate of successfully synthesizing BMS-477118.Wherein the synthesis of adamantane compound I mainly adopts enzyme catalysis ammonification also originally to build its chiral centre (reference WO2010032129A at present; US2005090539; Adv.Syn.Cat., 2007,349:1369-1378; Bioorganic.Med.Chem, 2011,19 (3): 1136-1154; US2010291642 etc.).Synthetic route is as follows:
Although the method for enzyme catalysis ammonification reduction has the advantage of transformation efficiency high (about 99%) and selectivity good (ee>99%) mutually, but biological enzyme technology is also immature, from the angle of synthetic chemistry, the manipulation of biological enzyme still has certain difficulty.
Also document is had to adopt the method for chemical resolution to carry out synthetic compound (I) (with reference to J.Med.Chem, 2005,48:5025; WO2011117393; US2005090539).Document J.Med.Chem, disclosed in 2005,48:5025, synthetic route is as follows:
This method also can synthetic compound (I), but the disadvantage of this quadrat method is that the oxidizing condition of final step is harsh, has a large amount of dihydroxyl and trihydroxy-impurity produces.Thus cause the separation and purification of Compound I very difficult, need to use post separation and just can take high purity product.This makes the yield of compound (I) extremely low, and preparation cost is high, is not suitable for amplifying production on a large scale.
Summary of the invention
In order to overcome the method for synthesizing adamantane amine compound in prior art, being difficult to the problem of scale operation, this application provides a kind of new synthesis and production method, to overcome the shortcoming of existing chemical resolution method.
First aspect of the present invention is to provide a kind of method of producing amantadine compound, and described amantadine compound (N-tertbutyloxycarbonyl-3-hydroxyl-1-adamantyl-D-glycine, CAS:361442-00-4) structure is as follows:
Described in the present invention first aspect, method comprises the steps:
Step 1,1-diamantane methyl alcohol carries out oxidizing reaction, obtains diamantane formaldehyde (A1);
Step 2, diamantane formaldehyde is Material synthesis intermediate (A2);
Step 3, with intermediate (A2) for Material synthesis amantadine compound (I).
Wherein, diamantane formaldehyde (A1) structural formula is as follows:
Wherein, intermediate (A2) structural formula is as follows:
In the first preferred embodiment in the present invention first, in step 1, the oxidizing reaction of 1-diamantane methyl alcohol is preferably Tempo oxidizing reaction, step comprises: at supercarbonate, 2,2, under 6,6-tetramethyl piperidine oxyradical and alkali metal bromide exist, react with hypochlorite.
In the first preferred embodiment in described first, in step 1, temperature of reaction is preferably-20 to 30 ° of C scopes, is preferably within the scope of-10 ° of C to 10 ° of C, is more preferably within the scope of-5 ° of C to 10 ° of C, be more preferably within the scope of 0 ° of C to 10 ° of C, be more preferably within the scope of 5 ° of C to 10 ° of C.
In the first preferred embodiment in described first, the termination time that step 1 is reacted can be judged by prior art by those skilled in the art, and the present invention is preferably 10-60min, is more preferably 15-50min, be more preferably 20-40min, as 25min, 30min etc.
Wherein, described in step 1, supercarbonate is preferably any one or a few in alkali metal hydrocarbonate, as saleratus, sodium bicarbonate or the mixing of the two, is more preferably sodium bicarbonate.
Wherein, alkali metal bromide described in step 1 is preferably Sodium Bromide, Potassium Bromide or the mixture of the two, is more preferably Sodium Bromide.
Wherein, described in step 1, hypochlorite is preferably alkaline metal hypochlorite, as potassium hypochlorite, clorox or the mixture of the two, is more preferably clorox.
In a kind of preferred embodiment in the present invention first, in step 1, order of addition(of ingredients) is as follows: first by 1-diamantane methyl alcohol and supercarbonate, 2,2,6,6-tetramethyl-piperidyl oxyradical, alkali metal bromide join in solvent, then add hypochlorite.
Should be understood that, various solid chemical compound described in step 1 can be add as a solution, or adds in solid form, unrestricted in the present invention.
In the first preferred embodiment of described first aspect, adding in hypochlorite process, temperature of reaction system preferably controls within the scope of-20 to 30 ° of C, be more preferably within the scope of-10 ° of C to 10 ° of C, be more preferably within the scope of-5 ° of C to 10 ° of C, be more preferably within the scope of 0 ° of C to 10 ° of C, be more preferably within the scope of 5 ° of C to 10 ° of C.
In the first preferred embodiment of described first aspect, solvent described in step 1 can be any one or a few the mixture in water and organic solvent, such as water and dichloromethane mixture.
In the first preferred embodiment of described first aspect, in step 1, the collection method of reaction product is preferably: collected organic layer, and uses saturated sodium sulfite solution washing, except desolventizing.
More preferably, in the described process except desolventizing, temperature preferably no more than 50 ° of C, more preferably less than 45 ° of C.
In the second preferred embodiment in the present invention first, step 2 can be prepare with disclosed method in prior art, as document J.Med.Chem, and method disclosed in 2005,48:5025.
In the third preferred embodiment in the present invention first, step 3 can be prepare with disclosed method in prior art, as document J.Med.Chem, and method disclosed in 2005,48:5025.But be preferably, step 3 reactions steps comprises:
Step 3.1, in concentrated sulfuric acid, adds nitric acid and intermediate (A2) reacts;
Step 3.1 gained reaction solution adjust ph is the alkaline condition of 14 or higher by step 3.2, and add tert-Butyl dicarbonate (BOC acid anhydrides), adjust ph is to 3-4; Continue reaction;
Step 3.3, reaction terminates rear separation synthetic product, obtains amantadine compound (I).
In the present invention first in the third preferred embodiment, described in step 3.1 of the present invention, the vitriol oil is preferably the sulfuric acid of mass concentration >=90%, is preferably the sulfuric acid of >=95%, most preferably is the sulfuric acid of 98%.
In the present invention first in the third preferred embodiment, described in step 3.1 of the present invention, nitric acid preferred concentration is 3-20mol/L, is more preferably 5-15mg/L, is more preferably 8-13mol/L, as 10mol/L, 12mol/L.
In the present invention first in the third preferred embodiment, in step 3.1 of the present invention, temperature of reaction is preferably 15-40 ° of C, is more preferably 20-35 ° of C, is more preferably 25-30 ° of C, such as, can be to react under room temperature.
In the third preferred embodiment in the present invention first, step 3.1 charging process is preferably: joined in the vitriol oil by nitric acid, and control temperature is no more than 40 ° of C, preferably no more than 35 ° of C, more preferably less than 30 ° of C; Then intermediate A 2 is added.
In the third preferred embodiment in the present invention first, in step 3.1, the reaction terminating time can be judged by prior art by those skilled in the art, in the present invention, the step 3.1 preferred reaction times is 12-36h, is more preferably 15-24h, as 18h, 20h etc.
In the present invention first in the third preferred embodiment, in step 3.2, adjust ph is in alkaline procedures, preferably uses any one or a few in sodium hydroxide, potassium hydroxide or ammoniacal liquor, is more preferably sodium hydroxide.
In the present invention first in the third preferred embodiment, in step 3.2, adjust ph is in 3-4 process, preferably uses any one or a few the mixing in hydrochloric acid, sulfuric acid, nitric acid, and is preferably hydrochloric acid.
In the third preferred embodiment in the present invention first, in step 3.2, the reaction terminating time can be judged by prior art by those skilled in the art, in the present invention, the step 3.2 preferred reaction times is 12-36h, is more preferably 15-24h, as 18h, 20h etc.
In the present invention first in the third preferred embodiment, in step 3.3, reaction product collection method is preferably: collect the organic layer that reaction terminates rear system, recrystallization obtains amantadine compound (I).
In the third preferred embodiment in described first, in step 3.3, recrystallization solvent is preferably acetonitrile.
In the 4th kind of preferred embodiment in the present invention first, step 3 working method most preferably is:
Step 3.1, in concentrated sulfuric acid, adds nitric acid and intermediate (A2) reacts;
Step 3.2, be poured into water by step 3.1 gained reaction solution, adjust ph is the alkaline condition of 14 or higher, and add tert-Butyl dicarbonate (BOC acid anhydrides), adjust ph is to 3-4; Add organic solvent and continue reaction;
Step 3.3, reaction terminates rear separation synthetic product, obtains amantadine compound (I).
In the 4th kind of preferred embodiment in described first, organic solvent is preferably not miscible with water solvent, as ethyl acetate, butylacetate etc., is preferably ethyl acetate.
The present invention second aspect is to provide a kind of method of producing BMS-477118, comprises the steps:
Step 1, by any means synthesizing amantadine (I) described in the present invention first aspect;
Step 2, amantadine (I) and Pyrrolidine amide compound (II) are obtained by reacting BMS-477118.
Should be understood that:
In any means that the present invention is above-mentioned, the mol ratio that between reactant, molar ratio can be selected between the next reactant of ideal response state by those skilled in the art, in order to fast reaction speed also can be that a certain reactant molar ratio is excessive.In any means that the present invention is above-mentioned, catalyst levels can by those skilled in the art's selective catalysis amount.
Any synthetic method described in the present invention first aspect and various preferred embodiment, all unrestrictedly can be applied to the present invention second aspect.
The above-mentioned all respects of the present invention and various preferred embodiment, unrestrictedly can carry out arbitrary combination by those skilled in the art.
The present invention with 1-diamantane methyl alcohol for raw material, through oxidation, docking, hydrolysis, hydrogenation, hydroxylation and amido protecting totally 6 steps reactions realize the synthesis of amantadine compound (I).Wherein the Swern oxidation of this project former is improved to 2 of innovation by the first step oxidizing reaction, 2,6,6-tetramethyl-piperidyl oxyradical (Tempo) is oxidized, make this step react the reaction conditions overcoming the harshness of low-temperature deep anhydrous and oxygen-free, and its yield and purity are greatly improved.
Have employed the method for oxidation of innovation from compd A 2 to compound (I), and last 2 steps can be incorporated with one kettle way, yield and purity have had very large breakthrough.
Production method provided by the invention, rational technology, simple to operate, environmentally friendly; Whole reaction process mild condition, without the reaction of harsh anhydrous and oxygen-free.
The method that this aspect provides successfully has synthesized the adamantane compound with high optical activity (I) in a large number with high yield, ee>99%.
Accompanying drawing explanation
Fig. 1 is the synthetic route chart that the first preferred embodiment of the present invention produces amantadine;
Fig. 2 is the synthetic route chart that the second preferred embodiment of the present invention produces amantadine.
Embodiment
With reference to Fig. 1, the method for production amantadine compound (I) of the present invention is described in detail and is described in conjunction with the embodiments.
Embodiment 1
step 1
According to document J.Med.Chem, method disclosed in 2005,48:5025,1-diamantane methanol oxidation obtains diamantane formaldehyde (A1).
step 2
According to document J.Med.Chem, method disclosed in 2005,48:5025, with diamantane formaldehyde (A1) for raw material, through docking with 2-amino-2-phenylethyl alcohol (CAS:7568-92-5, DL-benzene glycinol), is hydrolyzed, obtains intermediate (A2) after hydrogenation.
step 3
Drop into 98wt% sulfuric acid (12.5L) in 30L reactor, be cooled to 10 ° of C, drip 10N nitric acid (1.8L), in dropping process, temperature is no more than 30 ° of C; In reaction solution, drop into diamantane intermediate A 2(2.5kg in batches)), add time 1h; Stirring at room temperature 18h.
Reaction solution is poured in 125L water, and 50% sodium hydroxide solution regulates reacting liquid pH value to 14; Add BOC acid anhydrides (11Kg), stirring at room temperature 18h, with 1N salt acid for adjusting pH value within the scope of 3-4, add 75L ethyl acetate, stir 30min.
Leave standstill; Lower floor abandons, and organic layer 55 ° of C water-baths concentrate; Add recrystallized from acetonitrile in enriched material and obtain diamantane intermediate (I) 2.0Kg, yield 80%, ee>99%.
Embodiment 2
step 1
1-diamantane methyl alcohol (250g, 1.5mol, CAS:770-71-8), methylene dichloride (1.25L), sodium bicarbonate (63.25g is dropped in 5L four-hole bottle, 0.75mol), water (380g), 2,2,6,6-tetramethyl piperidine oxyradical (Tempo, catalytic amount, as 2.5g, CAS:2564-83-2), Sodium Bromide (31g, 0.3mol), open and stir, cryosel bath is by ° C of temperature drop to 0 ± 5 in system; Drip chlorine bleach liquor (10wt%, 1.8kg), in dropping process, keep system temperature to be no more than 10 ° of C; Insulated and stirred 0.5h, leave standstill, separate lower floor, upper strata abandons: lower floor adds saturated sodium bisulfite solution 1L, stirs 15min, and leave standstill, upper strata abandons; Collect lower floor's concentrating under reduced pressure, bath temperature more than 45 ° of C, must not obtain yellow oil diamantane formaldehyde (A1) 237.5g, yield 95%.
step 2
According to document J.Med.Chem, method disclosed in 2005,48:5025, with diamantane formaldehyde (A1) for raw material, through docking with 2-amino-2-phenylethyl alcohol (CAS:7568-92-5, DL-benzene glycinol), is hydrolyzed, obtains intermediate (A2) after hydrogenation.
step 3
Drop into 98wt% sulfuric acid (12.5L) in 30L reactor, be cooled to 10 ° of C, drip 10N nitric acid (1.8L), in dropping process, temperature is no more than 30 ° of C; In reaction solution, drop into diamantane intermediate A 2(2.5kg in batches)), add time 1h; Stirring at room temperature 18h.
Reaction solution is poured in 125L water, and 50% sodium hydroxide solution regulates reacting liquid pH value to 14; Add BOC acid anhydrides (11Kg), stirring at room temperature 18h, with 1N salt acid for adjusting pH value within the scope of 3-4, add 75L ethyl acetate, stir 30min.
Leave standstill; Lower floor abandons, and organic layer 55 ° of C water-baths concentrate; Add recrystallized from acetonitrile in enriched material and obtain diamantane intermediate (I) 2.0Kg, yield 80%, ee>99%.
Embodiment 3
By amantadine compound (I) prepared by embodiment 1 or 2, conventionally (can reference WO2011117393A, WO2010032129A, US20060035954, US2005090539; And J.Med.Chem, 2005,48:5025-5037 and Org.Process.Res.Dev, 2009,13:1169-1176) with Pyrrolidine amide compound (II) ((1S, 3S, 5S)-2-azabicyclo [3.1.0] hexane-3-methane amide, CAS:361440-68-8) reaction acquisition BMS-477118 (III).
Be described in detail specific embodiments of the invention above, but it is just as example, the present invention is not restricted to specific embodiment described above.To those skilled in the art, any equivalent modifications that the present invention is carried out and substituting also all among category of the present invention.Therefore, equalization conversion done without departing from the spirit and scope of the invention and amendment, all should contain within the scope of the invention.
Claims (9)
1. produce a method for amantadine compound, described amantadine compound structure is as follows:
It is characterized in that, comprise the steps:
Step 1,1-diamantane methyl alcohol carries out oxidizing reaction, obtains diamantane formaldehyde (A1);
Step 2, diamantane formaldehyde is Material synthesis intermediate (A2);
Step 3, with intermediate (A2) for Material synthesis amantadine compound (I);
Wherein, diamantane formaldehyde (A1) structural formula is as follows:
Wherein, intermediate (A2) structural formula is as follows:
Wherein,
In step 1, the oxidizing reaction of 1-diamantane methyl alcohol is Tempo oxidizing reaction, and step comprises: under supercarbonate, 2,2,6,6-tetramethyl piperidine oxyradicals and alkali metal bromide exist, react with hypochlorite;
Step 3 reactions steps comprises:
Step 3.1, in concentrated sulfuric acid, adds nitric acid and intermediate (A2) reacts;
Step 3.2, be the alkaline condition of 14 or higher by step 3.1 gained reaction solution adjust ph, add tert-Butyl dicarbonate, adjust ph is to 3-4; Continue reaction;
Step 3.3, reaction terminates rear separation synthetic product, obtains amantadine compound (I).
2. method according to claim 1, is characterized in that, in step 3.1, temperature of reaction is 15-40 DEG C.
3. method according to claim 1, is characterized in that, step 3.1 charging process is: joined in the vitriol oil by nitric acid, and control temperature is no more than 40 DEG C; Then intermediate (A2) is added.
4. method according to claim 1, is characterized in that, the reaction times of step 3.1 or step 3.2 is 10-36h.
5. method according to claim 1, is characterized in that, in step 3.3, reaction product collection method is: collect the organic layer that reaction terminates rear system, recrystallization obtains amantadine compound (I).
6. method according to claim 5, is characterized in that, recrystallization solvent is acetonitrile.
7. method according to claim 1, is characterized in that, in step 1 temperature of reaction be-20 DEG C within the scope of 30 DEG C.
8. method according to claim 1, is characterized in that, in step 1, the reaction times is 10-60min.
9. produce a method for BMS-477118, it is characterized in that, comprise the steps:
Step 1, by method synthesizing amantadine (I) described in claim 1;
Step 2, amantadine (I) and Pyrrolidine amide compound (II) are obtained by reacting BMS-477118; Wherein, the structural formula of Pyrrolidine amide compound (II) is as follows:
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103467361A (en) * | 2013-09-09 | 2013-12-25 | 嘉兴学院 | Morpholine derivative with S-proline in cyclopropane structure and preparation method thereof |
| 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 |
| 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 diamantane 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 | Preparation method of 1,3-adamantane dicarboxylic acid |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 | Preparation method of 1,3-adamantane dicarboxylic acid |
Non-Patent Citations (1)
| Title |
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| Discovery and Preclinical Profile of Saxagliptin (BMS-477118): A Highly Potent, Long-Acting, Orally Active Dipeptidyl Peptidase IV Inhibitor for the Treatment of Type 2 Diabetes;David J.Augeri et al.;《J.Med.Chem.》;20050624;第48卷;第5025-5037页 * |
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