CN108299252A - A kind of synthetic method of Norepinephrine Salonc Acid metabolite - Google Patents
A kind of synthetic method of Norepinephrine Salonc Acid metabolite Download PDFInfo
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- CN108299252A CN108299252A CN201810299571.8A CN201810299571A CN108299252A CN 108299252 A CN108299252 A CN 108299252A CN 201810299571 A CN201810299571 A CN 201810299571A CN 108299252 A CN108299252 A CN 108299252A
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- norepinephrine
- salonc
- synthetic method
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/24—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfuric acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C247/00—Compounds containing azido groups
- C07C247/02—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton
- C07C247/08—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton being unsaturated
- C07C247/10—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton being unsaturated and containing rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/63—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/64—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of functional groups containing oxygen only in singly bound form
Abstract
The invention discloses a kind of synthetic methods of Norepinephrine Salonc Acid metabolite, belong to pharmaceutical synthesis field, and this method, for starting material, synthesizes to obtain with 3,4 resacetophenones through six-step process.The present invention filters out optimal preparation process and reaction condition by many experiments, and entire technological design is reasonable, and operability is strong, the product that the present invention is prepared, and for chemical purity up to 98.5% or more, whole yield is relatively high.The Norepinephrine Salonc Acid metabolite that the present invention is prepared(DL‑Norepinephrine 4‑Sulfate), standard items are provided for the research of the metabolic mechanism of adrenaline and norepinephrine class drug, can be used for probing into the metabolic process of the drug in vivo, there is great application study value in CLINICAL PHARMACOKINETIS STUDY ON.
Description
Technical field
The invention belongs to pharmaceutical synthesis field more particularly to a kind of synthesis sides of Norepinephrine Salonc Acid metabolite
Method.
Background technology
Adrenaline is a kind of hormone and neurotransmitter, is discharged by adrenal gland;It is a kind of hormone gone out by human secretory.
Adrenaline can be such that cardiac contractile force rises, make heart, liver and the blood vessel dilatation of muscles and bones and skin, mucous membrane vessel retraction, be
The necessary article of dying human or animal is saved, chemistry is entitled(R)-4-(2-(Methylamino)- 1- hydroxyethyls] -1,2- benzene two
Phenol, clinic are mainly used for heart arrest, bronchial asthma, anaphylactic shock, can also treat nettle rash, hay fever and schneiderian membrane or
Gingiva bleeding gingival hemorrhage.
Norepinephrine, scientific name 1- (3,4- dihydroxyphenyl) -2- ethylaminoethanols, are after adrenaline removes N- methyl
The substance of formation, also belongs to catecholamine in chemical constitution, is once called as " Norepinephrine ", for treat acute myocardial infarction,
Low blood pressure caused by extracorporal circulatory system, pheochromocytoma excision etc.;The auxiliary treatment of the molten amount of blood is supplemented when this product is as first aid;Also may be used
The poly- blood pressure maintenance after stopping recovery of low blood pressure and heartbeat when for treating block inside vertebral canal.
With the progress in epoch, the raising of scientific and technological level, people to drug before marketing drugs to that must carry out quality, safety
Property and the importance etc. of efficiency scientific evaluation, which have, more fully to be recognized, therefore, to the metabolic process research of drug in vivo
It is essential.The metabolic process of drug is increasingly paid attention to by medical personal during drug development.This
Invent obtained Norepinephrine Salonc Acid metabolite(DL-Norepinephrine 4-Sulfate), be adrenaline and
The metabolic mechanism research of norepinephrine class drug provides standard items, can be used for probing into the metabolism of the drug in vivo
Journey, in CLINICAL PHARMACOKINETIS STUDY ON have great application study value, but the prior art it is traditional method yield it is non-
It is often low, only 2%, it is mentioned as by-product, and purification is cumbersome, cannot largely synthesize.
Invention content
The present invention provides a kind of synthetic method of Norepinephrine Salonc Acid metabolite, synthetic method energy of the invention
It is enough in a series of synthesis of sulfonic acid metabolins, technological design is reasonable, and operability is strong, and high income is, it can be achieved that industrialized production.
In order to achieve the above object, the present invention uses following technical scheme:
A kind of synthetic method of Norepinephrine Salonc Acid metabolite, includes the following steps:
(1)Compound I is taken, highly basic and benzyl protection agent is added, at a temperature of 20 DEG C -60 DEG C, is reacted 12-48 hours, in obtaining
Mesosome II;
(2)Intermediate II is dissolved in non-protonic solvent, bromide reagent bromination is added, at a temperature of 5 DEG C of -40 DEG C of degree, reaction
10-48 hours, obtain intermediate product III;
(3)Intermediate III is reacted with reaction of sodium azide at a temperature of 20 DEG C -40 DEG C in polar aprotic solvent
12-48 hours, obtain intermediate product IV;
(4)Intermediate product IV is dissolved in non-protonic solvent, and pyridine. sulfur trioxide is added, at a temperature of 20 DEG C -60 DEG C, reaction
Obtain intermediate product V within 10-48 hours;
(5)It takes intermediate product V to be dissolved in protonic solvent, reducing agent is added, at a temperature of 5 DEG C -25 DEG C, react 10-24 hours,
Obtain intermediate VI;
(6)It takes intermediate product VI to be dissolved in protonic solvent, at a temperature of 20 DEG C -40 DEG C, catalyst, 15Psi-40Psi is added
Under pressure, catalytic hydrogenation reacts 5-24 hours, and reduction azido obtains target product VII to amino.
In step described above, step (1) described highly basic is sodium hydride, sodium hydroxide or potassium hydroxide, preferred sodium hydride,
The addition of the highly basic is 2-4 equivalents, and the benzyl protection reagent is cylite or benzyl chloride, and preferred benzyl chloride is described
Benzyl protection reagent dosage be 0.8-1.5 equivalents, preferably 40 DEG C of reaction temperature, preferably 48 hours reaction time;Step (2)
The bromide reagent is tetrabutyl tribromide ammonium or N- bromo-succinimides, preferably tetrabutyl tribromide ammonium, the bromination examination
Agent addition is 0.8-1.2 equivalents, and the non-protonic solvent is tetrahydrofuran, carbon tetrachloride or acetonitrile, preferably tetrahydrochysene furan
It mutters;Step (3) described polar non-solute is dimethyl sulfoxide or n,N-Dimethylformamide, and preferred dimethyl sulfoxide is described folded
The addition of sodium nitride is 1-1.5 equivalents, preferably 40 DEG C of reaction temperature, preferably 12 hours reaction time;Step (4) the non-matter
Sub- property solvent is dichloromethane, acetonitrile or tetrahydrofuran, preferably dichloromethane, and the addition of the pyridine. sulfur trioxide is 1-3
Equivalent, preferably 40 DEG C of reaction temperature;Protonic solvent described in step (5) is methanol or ethyl alcohol, preferably methanol, and described goes back
Former agent is sodium borohydride or lithium borohydride, preferably sodium borohydride;The addition of the reducing agent is 0.05-0.3 equivalents;Step
(6) protonic solvent described in is methanol, ethyl alcohol or water, preferably water, and the catalyst is palladium carbon, the addition of the catalyst
Amount is 0.05-0.3 equivalents, preferably 40 DEG C of reaction temperature.
Beneficial effects of the present invention:The present invention provides a kind of synthetic method of Norepinephrine Salonc Acid metabolite,
The present invention can very easily obtain a large amount of product using comparatively cheap raw material by six-step process, and this method obtains
Product, sulfonic position can only on fixed position 4, avoid on another position 3.This method does not have
It has been reported that reaction condition is milder, processing is simple, and yield is relatively high, obtained product chemistry purity up to 98.5% with
On, technological design is reasonable, and operability is strong, it can be achieved that industrialized production.
Description of the drawings
Fig. 1 is the reacting flow chart of synthetic method of the present invention.
Specific implementation mode
Embodiment 1
It is as shown in Figure 1 the reacting flow chart of the present invention:
(1)By 12 g sodium hydrides(60 %)It is suspended in 80 mL DMSO, 20 gization bought are added in ice bath stirring 0.5 hour
Object I is closed, is stirred at room temperature 5 hours, then to addition 17g benzyl chlorides in reaction solution, waits being added dropwise, react at room temperature 24 hours;To anti-
It answers and 200 mL water is added in liquid, extracted with dichloromethane, concentrate dichloromethane phase, column chromatography purifies to obtain 18 g intermediate IIs,
White solid.
(2)16 g intermediate IIs are dissolved in 240 mL tetrahydrofurans, 34 g tetrabutyl tribromide ammoniums, room is added in room temperature
Temperature reaction 24 hours, obtains red suspension;Solvent is spin-dried for, 200 mL water are added, are extracted with ethyl acetate, concentrates acetic acid second
Ester phase, column chromatography purification, obtains 14 g intermediate IIIs, off-white powder.
(3)14 g intermediate IIIs are dissolved in 56 mL dimethyl sulfoxides, 3.5 g sodium azide are added, reacted at room temperature
Night obtains yellow suspension, and 200 mL water are added into reaction solution, are extracted with dichloromethane, washes twice, dichloromethane phase
Concentration obtains 8.5 g intermediate compound IVs, off-white powder after column chromatography purification.
(4)8.5 g intermediate compound IVs are dissolved in 60 mL dichloromethane, 6g pyridine. sulfur trioxides are then added, room temperature is anti-
It should stay overnight, obtain yellow solution, reaction solution is spin-dried for, column chromatography purifies to obtain 9g intermediates, red oil.
(5)8g intermediates V is dissolved in 160 mL methanol, under condition of ice bath, 1.6 g sodium borohydrides, room temperature is added portionwise
Reaction 24 hours, obtains the solution of yellow, reaction solution is concentrated, and column chromatography purification obtains 4.5 g intermediate VI, off-white color is solid
Body.
(6)0.5 g intermediates VI is dissolved in 10 mL water, under condition of ice bath, 10% palladium carbons of 0.05g, hydrogen is added
Then 40 psi of pressure is reacted at room temperature 24 hours, filtering is lyophilized filtrate, obtains the pure target product VII of 0.3 g, yellow is solid
Body, 98.6 % of HPLC purity.
1H NMR (400 MHz, DMSO-d6): δ 7.06-7.03 (d, 1H), 6.79-6.79 (d, 1H),
6.71-6.68 (dd, 1H), 5.36 (br, 1H),4.39 (m, 1H), 2.73-2.68 (m, 1H), 2.62-2.56
(m, 1H). MS: 248.1[M-1]-。
Embodiment 2
It is as shown in Figure 1 the reacting flow chart of the present invention:
(1)By 12 g sodium hydrides(60 %)It is suspended in 80 mL DMSO, 20 gization bought are added in ice bath stirring 0.5 hour
Object I is closed, is stirred at room temperature 5 hours, then to addition 16g benzyl chlorides in reaction solution, waits being added dropwise, react at room temperature 24 hours;To anti-
It answers and 200 mL water is added in liquid, extracted with dichloromethane, concentrate dichloromethane phase, column chromatography purifies to obtain 18 g intermediate IIs,
White solid.
(2)16 g intermediate IIs are dissolved in 240 mL carbon tetrachloride, it is sub- that 34 g N- bromos succinyl are added in room temperature
Amine reacts at room temperature 30 hours, obtains red suspension;Solvent is spin-dried for, 200 mL water are added, are extracted with ethyl acetate, is concentrated
Ethyl acetate phase, column chromatography purification, obtains 14 g intermediate IIIs, off-white powder.
(3)14 g intermediate IIIs are dissolved in 56 mLN, in dinethylformamide, 3.5 g sodium azide, room is added
Temperature reaction overnight, obtains yellow suspension, 200 mL water is added into reaction solution, are extracted with dichloromethane, washes twice, two
Chloromethanes mutually concentrates, and 8.5 g intermediate compound IVs, off-white powder are obtained after column chromatography purification.
(4)8.5 g intermediate compound IVs are dissolved in 60 mL tetrahydrofurans, 6g pyridine. sulfur trioxides are then added, room temperature is anti-
It should stay overnight, obtain yellow solution, reaction solution is spin-dried for, column chromatography purifies to obtain 9g intermediates, red oil.
(5)8g intermediates V is dissolved in 160 mL ethyl alcohol, under condition of ice bath, 1.6 g lithium borohydrides, room temperature is added portionwise
Reaction 24 hours, obtains the solution of yellow, reaction solution is concentrated, and column chromatography purification obtains 4.5 g intermediate VI, off-white color is solid
Body.
(6)0.5 g intermediates VI is dissolved in 10 mL water, under condition of ice bath, 10% palladium carbons of 0.05g, hydrogen is added
Then 30 psi of pressure is reacted at room temperature 20 hours, filtering is lyophilized filtrate, obtains the pure target product VII of 0.3 g, yellow is solid
Body, 98.6 % of HPLC purity.
1HNMR (400 MHz, DMSO-d6): δ 7.06-7.03 (d, 1H), 6.79-6.79 (d, 1H),
6.71-6.68 (dd, 1H), 5.36 (br, 1H),4.39 (m, 1H), 2.73-2.68 (m, 1H), 2.62-2.56
(m, 1H). MS: 248.1[M-1]-。
Embodiment 3
It is as shown in Figure 1 the reacting flow chart of the present invention:
(1)By 12 g sodium hydroxides(60 %)It is suspended in 80 mL DMSO, 20 g bought are added in ice bath stirring 0.5 hour
Compound I is stirred at room temperature 5 hours, then to addition 16g cylites in reaction solution, waits being added dropwise, react at room temperature 24 hours;To
200 mL water are added in reaction solution, are extracted with dichloromethane, concentrate dichloromethane phase, column chromatography purifies to obtain 18 g intermediates
II, white solid;
(2)16 g intermediate IIs are dissolved in 240 mL acetonitriles, 34 g N- bromo-succinimides are added in room temperature, and room temperature is anti-
It answers 30 hours, obtains red suspension;Solvent is spin-dried for, 200 mL water are added, are extracted with ethyl acetate, concentrates ethyl acetate
Phase, column chromatography purification, obtains 14 g intermediate IIIs, off-white powder.
(3)14 g intermediate IIIs are dissolved in 56 mLN, in dinethylformamide, are added 3.5 g sodium azide, 40
DEG C reaction overnight, obtain yellow suspension, 200 mL water be added into reaction solution, are extracted with dichloromethane, wash twice, two
Chloromethanes mutually concentrates, and 8.5 g intermediate compound IVs, off-white powder are obtained after column chromatography purification.
(4)8.5 g intermediate compound IVs are dissolved in 60 mL dichloromethane, 6g pyridine. sulfur trioxides are then added, 40 DEG C anti-
It should stay overnight, obtain yellow solution, reaction solution is spin-dried for, column chromatography purifies to obtain 9g intermediates, red oil.
(5)8g intermediates V is dissolved in 160 mL ethyl alcohol, under condition of ice bath, is added portionwise 1.6 g lithium borohydrides, 10 DEG C
Reaction 18 hours, obtains the solution of yellow, reaction solution is concentrated, and column chromatography purification obtains 4.5 g intermediate VI, off-white color is solid
Body.
(6)0.5 g intermediates VI is dissolved in 10 mL water, under condition of ice bath, 10% palladium carbons of 0.05g, hydrogen is added
Then 20 psi of pressure is reacted at room temperature 20 hours, filtering is lyophilized filtrate, obtains the pure target product VII of 0.3 g, yellow is solid
Body, 98.6 % of HPLC purity.
1H NMR (400 MHz, DMSO-d6): δ 7.06-7.03 (d, 1H), 6.79-6.79 (d, 1H),
6.71-6.68 (dd, 1H), 5.36 (br, 1H),4.39 (m, 1H), 2.73-2.68 (m, 1H), 2.62-2.56
(m, 1H). MS: 248.1[M-1]-。
The above is only a preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
For member, various improvements and modifications may be made without departing from the principle of the present invention, these improvements and modifications are also answered
It is considered as protection scope of the present invention.
Claims (13)
1. a kind of synthetic method of Norepinephrine Salonc Acid metabolite, which is characterized in that include the following steps:
(1)Compound (I) is taken, highly basic and benzyl protection agent is added, at a temperature of 20 DEG C -60 DEG C, reacts 12-48 hours, obtains
Intermediate (II);
(2)Intermediate (II) is dissolved in non-protonic solvent, bromide reagent bromination is added, at a temperature of 5 DEG C of -40 DEG C of degree, instead
It answers 10-48 hours, obtains intermediate product (III);
(3)By intermediate(III)It is reacted at a temperature of 20 DEG C -40 DEG C with reaction of sodium azide in polar aprotic solvent
12-48 hours, obtain intermediate product (IV);
(4)Intermediate product(IV)It is dissolved in non-protonic solvent, pyridine. sulfur trioxide is added, at a temperature of 20 DEG C -60 DEG C, reaction
Obtain within 10-48 hours intermediate product (V);
(5)Take intermediate product(V)It is dissolved in protonic solvent, reducing agent is added, at a temperature of 5 DEG C -25 DEG C, reaction 10-24 is small
When, obtain intermediate(VI);
(6)Take intermediate product(VI)It is dissolved in protonic solvent, at a temperature of 20 DEG C -40 DEG C, catalyst, 15Psi- is added
Under 40Psi pressure, catalytic hydrogenation reacts 5-24 hours, and reduction azido obtains target product to amino(VII).
2. the synthetic method of Norepinephrine Salonc Acid metabolite according to claim 1, which is characterized in that step
(1) highly basic is sodium hydride, sodium hydroxide or potassium hydroxide, and the addition of the highly basic is 2-4 equivalents, and the benzyl is protected
It is cylite or benzyl chloride to protect reagent, and the addition of the benzyl protection agent is 0.8-1.5 equivalents.
3. the synthetic method of Norepinephrine Salonc Acid metabolite according to claim 1 or 2, which is characterized in that step
Suddenly (1) described highly basic is sodium hydride, and the benzyl protection reagent is benzyl chloride.
4. the synthetic method of Norepinephrine Salonc Acid metabolite according to claim 1, which is characterized in that step
(2) bromide reagent is tetrabutyl tribromide ammonium or N- bromo-succinimides, and the bromide reagent addition is 0.8-1.2
Equivalent, the non-protonic solvent are tetrahydrofuran, carbon tetrachloride or acetonitrile.
5. the synthetic method of Norepinephrine Salonc Acid metabolite according to claim 1 or 4, which is characterized in that step
Suddenly (2) described bromide reagent is tetrabutyl tribromide ammonium, and the non-protonic solvent is tetrahydrofuran.
6. the synthetic method of Norepinephrine Salonc Acid metabolite according to claim 1, which is characterized in that step
(3) polar non-solute is dimethyl sulfoxide or n,N-Dimethylformamide, and the sodium azide addition is worked as 1-1.5
Amount.
7. the synthetic method of Norepinephrine Salonc Acid metabolite according to claim 1 or 6, which is characterized in that step
Suddenly (3) described polar non-solute is dimethyl sulfoxide.
8. the synthetic method of Norepinephrine Salonc Acid metabolite according to claim 1, which is characterized in that step
(4) non-protonic solvent is dichloromethane, acetonitrile or tetrahydrofuran, and the pyridine. sulfur trioxide addition is 1-3 equivalents.
9. the synthetic method of the Norepinephrine Salonc Acid metabolite according to claim 1 or 8, which is characterized in that step
Suddenly (4) described non-protonic solvent is dichloromethane.
10. the synthetic method of Norepinephrine Salonc Acid metabolite according to claim 1, which is characterized in that step
(5) protonic solvent described in is methanol or ethyl alcohol, and the reducing agent is sodium borohydride or lithium borohydride, and the reducing agent adds
It is 1-3 equivalents to enter amount.
11. the synthetic method of the Norepinephrine Salonc Acid metabolite according to claim 1 or 10, which is characterized in that
Protonic solvent described in step (5) is methanol, and the reducing agent is sodium borohydride.
12. the synthetic method of Norepinephrine Salonc Acid metabolite according to claim 1, which is characterized in that step
(6) protonic solvent described in is methanol, ethyl alcohol or water, and the catalyst is palladium carbon, and the addition of the catalyst is 0.05-
0.3 equivalent.
13. the synthetic method of Norepinephrine Salonc Acid metabolite according to claim 1, which is characterized in that step
(1) reaction temperature is 40 DEG C, and the reaction time is 48 hours, and step (3) reaction temperature is 40 DEG C, and the reaction time is 12 small
When, step (4) described reaction temperature is 40 DEG C, and the reaction temperature described in step (6) is 40 DEG C.
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Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CN101035781A (en) * | 2004-09-09 | 2007-09-12 | 三菱制药株式会社 | 2-morpholino-4-pyrimidone compound |
WO2012168733A1 (en) * | 2011-06-10 | 2012-12-13 | Ucl Business Plc | Substituted 8 - amino - imidazo [1, 2-a] pyrazines as antibacterial agents |
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2018
- 2018-04-04 CN CN201810299571.8A patent/CN108299252A/en active Pending
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CN101035781A (en) * | 2004-09-09 | 2007-09-12 | 三菱制药株式会社 | 2-morpholino-4-pyrimidone compound |
WO2012168733A1 (en) * | 2011-06-10 | 2012-12-13 | Ucl Business Plc | Substituted 8 - amino - imidazo [1, 2-a] pyrazines as antibacterial agents |
Non-Patent Citations (5)
Title |
---|
CRISTIANO BOLCHI等: "Unichiral 2-(20-Pyrrolidinyl)-1,4-benzodioxanes: the 2R,20S Diastereomer of the N-Methyl-7-hydroxy Analogue Is a Potent α4β2-and α6β2-Nicotinic Acetylcholine Receptor Partial Agonist", 《J. MED. CHEM》 * |
DAVID A. LEARMONTH等: "Chemical Synthesis and Characterization of Conjugates of a Novel Catechol-O-methyltransferase Inhibitor", 《BIOCONJUGATE CHEM.》 * |
JAMES R. SAYER等: "2- and 3-substituted imidazo[1,2-a]pyrazines as inhibitors of bacterial type IV secretion", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
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