CN107001262A - The hemifumarate and its crystal formation of the proton pump inhibitor containing pyrrole ring, intermediate and medical usage - Google Patents
The hemifumarate and its crystal formation of the proton pump inhibitor containing pyrrole ring, intermediate and medical usage Download PDFInfo
- Publication number
- CN107001262A CN107001262A CN201580059766.XA CN201580059766A CN107001262A CN 107001262 A CN107001262 A CN 107001262A CN 201580059766 A CN201580059766 A CN 201580059766A CN 107001262 A CN107001262 A CN 107001262A
- Authority
- CN
- China
- Prior art keywords
- methyl
- pyrroles
- methylamino
- sulfonyl
- fluorophenyls
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
- C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
- C07C57/13—Dicarboxylic acids
- C07C57/15—Fumaric acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
- C07D207/48—Sulfur atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses hemifumarate, crystal formation and its intermediate and medical usage of the proton pump inhibitor containing pyrrole ring.Specifically, the present invention relates to a kind of hemifumarate of the proton pump inhibitor containing pyrrole ring, crystalline forms, intermediate and preparation method thereof and medical usage, (3 ((base of 2 (2 fluorophenyl) 4 ((methylamino) methyl) 1H pyrroles 1) sulfonyl) phenoxy group) N methylacetamide hemifumarates i.e. 2 shown in formula (I), and pass through 2 (3 ((base of 2 (2 fluorophenyl) 4 ((methylamino) methyl) 1H pyrroles 1) sulfonyl) phenoxy group) N methylacetamides and the salifying method of fumaric acid, and characterize hemifumarate crystal formation.The hemifumarate and its stability of crystal form of the present invention more preferably, and shows excellent bioactivity, with good hydrochloric acid in gastric juice inhibitory action.
Description
The present invention relates to field of pharmaceutical biology, and in particular to 2- (3- ((2- (2- fluorophenyls) -4- ((methylamino) methyl) -1H- pyrroles -1- bases) sulfonyl) phenoxy group)-N- methylacetamides hemifumarates and its crystal formation and preparation method, intermediate, pharmaceutical composition and its medical usage.
Peptic ulcer refers to the tissue damage more than muscular layer of mucosa that gastrointestinal mucosa is caused by peptic digest liquid autodigestion, gastral any position can be betided, it is wherein most commonly seen with stomach and duodenum, that is gastric ulcer and duodenal ulcer, its cause of disease, clinical symptoms and treatment method are substantially similar, clarify a diagnosis mainly by gastrocopy.Gastric ulcer is most common one kind in peptic ulcer, is primarily referred to as the tissue damage more than muscular layer of mucosa that stomach lining is caused by peptic digest liquid autodigestion.
Gastric ulcer is one of common disease, frequently-occurring disease in population of China.As the common type in peptic ulcer, the geographical distribution of gastric ulcer substantially has the north south to raise trend, and is apt to occur in the larger winter and spring of climate change.In addition, male's incidence of disease is apparently higher than women, may, work irregular with smoking, life and diet and ambient pressure and psychologic factors it is closely related.In recent years, the incidence of disease of gastric ulcer starts on a declining curve, but it still belongs to one of most common disease in disease of digestive system.Mainly loss of equilibrium is relevant between the damage factor and mucous membrane self-defense reparation factor of gastroduodenal mucous membrane for its generation.Helicobacter pylori (H.pylori) infection, NSAIDs (NSAID, such as aspirin), gastric acid secretion are the common disease factor for causing ulcer extremely.The characteristics of typical canker sores have chronicity, periodicity and rhythmicity.Wherein, it is apt to occur in small curved at stomach angle and antrum more gastric ulcer, is more common in Elderly male patient, it is fallen ill and seasonal variations have certain relation.
Stomach intracavitary, hydrochloric acid in gastric juice and pepsin are important digestion materials in gastric juice.Hydrochloric acid in gastric juice is highly acid material, with stronger aggressivity；Pepsin has the effect of aminosal, the protein that can be destroyed on coat of the stomach, however, in the presence of these factors of erosion, intestines and stomach remain to resist and maintain the integrality of mucous membrane and the function of itself, and it, which is primarily due to Grastiodudenal mucosa, also has series of defence and repair mechanism.We are by hydrochloric acid in gastric juice and the harmful erosion of pepsin
Property is referred to as damage mechanisms, and the defence that intestines and stomach itself are had and repair mechanism referred to as protection mechanism.It is now recognized that the protection mechanism of the gastroduodenal mucous membrane of normal person, it is sufficient to resist the erosion of hydrochloric acid in gastric juice and pepsin.But, when hydrochloric acid in gastric juice may occur for some link that some factors are compromised in protection mechanism and protease corrodes itself mucous membrane and causes the formation of ulcer.When excessive gastric acid secretion considerably beyond the defence and repair of mucous membrane may also cause ulcer.In recent years research is it has been shown that helicobacter pylori and NSAIDs are to damage stomach and intestine protection mechanism to cause the most commonly encountered diseases that ulcer is fallen ill because hydrochloric acid in gastric juice plays a crucial role in ulcer is formed.In addition, medicine, stress, hormone may also lead to the generation of ulcer, various psychological factors and bad dietary life habits can induced ulcer appearance.
Clinically mainly there are bisfentidine (H2-RA) and proton pump inhibitor (PPI) at present.H2-RA can suppress basis and the gastric acid secretion stimulated, conventional such as Cimetidine, ranitidine, famotidine and nizatidine；PPI acts on key enzyme H+-K+ATP enzyme of the parietal cell gastric acid secretion eventually in last step, makes its irreversible inactivation, and Acidinhibitor is stronger and persistent.PPI promotes speed, the healing rate of ulcer healing higher, treatment during NSAID can not be disabled suitable for various intractable ulcers or NSAID ulcers, Helicobacter pylori eradication for treatment can also be can be used for the synergy of antibiotic, therefore be the preferred medication of gastric ulcer.Conventional PPI has Omeprazole, Lansoprazole, Rabeprazole, esomeprazole, Iprazole etc..
2- (3- ((2- (2- fluorophenyls) -4- ((methylamino) methyl) -1H- pyrroles -1- bases) sulfonyl) phenoxy group)-N- methylacetamide hemifumarates are a kind of proton pump inhibitors containing pyrrole ring; it is notable with drug effect; the advantages of Small side effects, there are huge potentiality in treatment Gastric Ulcer Treatment.
The content of the invention
It is a kind of proton pump inhibitor containing pyrrole ring it is an object of the invention to provide the hemifumarate shown in a kind of formula (I), with treatment gastroesophageal reflux, peptic ulcer, gastric ulcer, duodenal bulbar ulcer, esophagitis etc..
Formula (I)
It is preferred that, the invention provides (3- ((2- (2- fluorophenyls)-the 4- ((first of the 2- shown in a kind of formula (1)
Amido) methyl) -1H- pyrroles -1- bases) sulfonyl) phenoxy group) and-N- methylacetamide hemifumarates crystal formation.
There are the XRD spectrum of the crystal formation (± 0.2 °) of 2 θ angles to be 7.858,9.456,13.202,14.836,15.099,15.749,15.050,19.948 characteristic peak, preferably, also containing 2 θ angles, (± 0.2 °) is 19.901,20.922,22.423,24.867 characteristic peak, particularly preferred, the XRD spectrum of the crystal formation is as shown in Figure 3.
Another object of the present invention is the preparation method for providing the hemifumarate crystal formation shown in a kind of formula (I), is obtained by (2) 2- (3- ((2- (2- fluorophenyls) -4- ((methylamino) methyl) -1H- pyrroles -1- bases) sulfonyl) phenoxy group)-N- methylacetamides with fumaric acid into salt crystallization in organic solvent.
It is preferred that, the preparation method comprises the following steps：
(1) formula (II) compound 2- (3- ((2- (2- fluorophenyls) -4- ((methylamino) methyl) -1H- pyrroles -1- bases) sulfonyl) phenoxy group)-N- methylacetamides are dissolved in organic solvent, add fumarate solid or fumaric acid solution；
(2) by above-mentioned reaction solution agitating and heating；
(3) cooling crystallization obtains formula (I) compound.
It is preferred that, the organic solvent is alcohols solvent.
It is preferred that, the alcohols solvent is selected from isopropanol or/and absolute ethyl alcohol.
It is preferred that, when alcohols solvent is isopropanol/absolute ethyl alcohol mixed solvent, wherein the ratio of isopropanol is 0.1%~100%.
It is preferred that, the alcohols solvent is the mixed solvent system of isopropanol/absolute ethyl alcohol, and the volume ratio of isopropanol/absolute ethyl alcohol is 1~8: 1, more preferably 3~5: 1, most preferably 4: 1.
It is preferred that, the fumaric acid solution is the ethanol solution of fumaric acid.
It is preferred that, the molar equivalent for adding fumaric acid is 0.4~0.5 equivalent of formula (II) compound, more preferably 0.45~0.47 equivalent.
It is preferred that, the temperature of step (2) agitating and heating is 50~82 DEG C, is more preferably flowed back
Temperature.
Another object of the present invention, which is also resided in, provides a kind of pharmaceutical composition comprising 2- (3- ((2- (2- fluorophenyls) -4- ((methylamino) methyl) -1H- pyrroles -1- bases) sulfonyl) phenoxy group)-N- methylacetamides hemifumarates and pharmaceutically acceptable carrier.
It is preferred that, the existence form of said composition is tablet or capsule.
Another object of the present invention also resides in offer 2- (3- ((2- (2- fluorophenyls) -4- ((methylamino) methyl) -1H- pyrroles -1- bases) sulfonyl) the phenoxy group)-N- methylacetamides hemifumarates or its crystal formation and described pharmaceutical composition and is preparing treatment gastroesophageal reflux; peptic ulcer; purposes in gastric ulcer, duodenal bulbar ulcer or esophagitis medicine.
Another object of the present invention also resides in the intermediate for providing and 2- (3- ((2- (2- fluorophenyls) -4- ((methylamino) methyl) -1H- pyrroles -1- bases) sulfonyl) phenoxy group)-N- methylacetamide hemifumarates being prepared shown in a kind of formula (III)
Another object of the present invention also resides in the method for providing and preparing the intermediate, including the tert-butyl group ((5- (2- fluorophenyls) -1H- pyrroles -3- bases) methyl) (methyl) carbonic ester is condensed in organic solvent with 3- (2- (methylamino) -2- oxoethoxies) phenyl -1- sulfonic acid chlorides obtained.
It is preferred that, the organic solvent is selected from benzene,toluene,xylene, acetonitrile or DMF.
Another object of the present invention also resides in a kind of method for preparing the intermediate free bases of offer, including the formula (III) compound is passed through into hydrogen chloride gas, and pH is adjusted to alkalescence with alkaline matter.
It is preferred that, the alkaline matter is selected from sodium acid carbonate, sodium hydroxide or sodium carbonate.
The hemifumarate stability of the present invention more preferably, and shows excellent bioactivity, with good hydrochloric acid in gastric juice inhibitory action.The compound crystal form is made in the present invention first, and gained crystal formation property is stable, pharmaceutical preparation application is especially suitable for, with good market prospects.
Fig. 1：The 1H-NMR collection of illustrative plates of 2- (3- ((2- (2- fluorophenyls) -4- ((methylamino) methyl) -1H- pyrroles -1- bases) sulfonyl) phenoxy group)-N- methylacetamide hemifumarates.
Fig. 2：The 13C-NMR collection of illustrative plates of 2- (3- ((2- (2- fluorophenyls) -4- ((methylamino) methyl) -1H- pyrroles -1- bases) sulfonyl) phenoxy group)-N- methylacetamide hemifumarates.
Fig. 3：The XRD spectrum of 2- (3- ((2- (2- fluorophenyls) -4- ((methylamino) methyl) -1H- pyrroles -1- bases) sulfonyl) phenoxy group)-N- methylacetamide hemifumarate crystal formations of the present invention.
Embodiment 1：
By 2- (3- ((2- (2- fluorophenyls) -4- ((methylamino) methyl) -1H- pyrroles -1- bases) sulfonyl) phenoxy group)-N- methylacetamides 10g, it is dissolved in the in the mixed solvent of isopropanol (80ml) and absolute ethyl alcohol (20ml), fumaric acid 1.26g is added under conditions of stirring, 50 DEG C are heated to afterwards to flow back 30 minutes, room temperature is naturally cooled under conditions of stirring, stirring 2 hours, filtering, it is dried to obtain 2- (3- ((2- (2- fluorophenyls) -4- ((methylamino) methyl) -1H- pyrroles -1- bases) sulfonyl) phenoxy group)-N- methylacetamide hemifumarates.
Embodiment 1-1
On the basis of embodiment 1, target crystal formation is obtained, crystal formation 1 is named as, weigh 9.8g, mass yield 98%, its 1H-NMR collection of illustrative plates is as shown in figure 1, XRD spectrum is as shown in Figure 3.
Embodiment 2：
By 2- (3- ((2- (2- fluorophenyls) -4- ((methylamino) methyl) -1H- pyrroles -1- bases) sulfonyl) phenoxy group)-N- methylacetamides 10g, it is dissolved in isopropanol (80ml), add the ethanol solution (1.26g/20ml) of fumaric acid, it is heated to backflow, solid all dissolves, room temperature is naturally cooled under conditions of stirring, stirring 2 hours, filtering, it is dried to obtain 2- (3- ((2- (2- fluorophenyls) -4- ((methylamino) methyl) -1H- pyrroles -1- bases) sulfonyl) phenoxy group)-N- methylacetamide hemifumarates.
Embodiment 2-1
On the basis of embodiment 2, target crystal formation is obtained, crystal formation 1 is named as, weigh 9.6g, mass yield 96%, its 1H-NMR collection of illustrative plates is substantially identical with Fig. 1, XRD spectrum is coincide with Fig. 3 substantially, meets the feature of crystal formation 1.
Embodiment 3：The preparation of 2- (3- ((2- (2- fluorophenyls) -4- ((methylamino) methyl) -1H- pyrroles -1- bases) sulfonyl) phenoxy group)-N- methylacetamide hemifumarate intermediates and free alkali
The first step
By the tert-butyl group ((5- (2- fluorophenyls) -1H- pyrroles -3- bases) methyl) (methyl) carbonic ester (3.0g, 10mmol) with 3- (2- (methylamino) -2- oxoethoxies) phenyl -1- sulfonic acid chlorides (2.64mg, 10mmol), add in acetonitrile, add DIEA stirring reactions 2~5 hours.Reaction solution cools, and adds watery hydrochloric acid regulation pH to 4~5, adds purified water crystallization, obtain compound III, 4.9g, yield：92.3%.
Second step
Compound III (4.5g) is dissolved in 15mL ethyl acetate, ice bath cools down reacting liquid temperature to 10 DEG C, puts into hydrogen chloride gas, stirring reaction 1 hour.PH is adjusted to alkalescence for sodium acid carbonate; washed with saturated nacl aqueous solution; anhydrous sodium sulfate drying; filtering; filtrate decompression is concentrated; gained residue is purified with eluant, eluent system B (n-hexane and ethyl acetate system) with silica gel column chromatography; obtain 2- (3- ((2- (2- fluorophenyls) -4- ((methylamino) methyl) -1H- pyrroles -1- bases) sulfonyl) phenoxy group)-N- methylacetamides (3.0g; colorless oil), yield：82.2%.
Experimental example 1, product stability research
2- (3- ((2- (2- fluorophenyls) -4- ((methylamino) methyl) -1H- pyrroles -1- bases) sulfonyl) phenoxy group)-N- methylacetamide hemifumarates, wherein fumaric acid content 11.80% is prepared with reference to the method for the embodiment of the present invention 1.
2- (3- ((2- (2- fluorophenyls) -4- ((methylamino) methyl) -1H- pyrroles -1- bases) sulfonyl) phenoxy group)-N- methylacetamide fumarates are prepared with reference to the method for the embodiment of the present invention 1; difference be to use in methanol/ethyl acetate alternative embodiment 1 into salt system, fumaric acid content is 21.10% in products obtained therefrom.
It is as follows that the above two salt of table 1 investigates result under the conditions of different affecting factors：
The antiulcer action of experimental example 2, rat Indomethacin Ulceration model evaluation hemifumarate
By healthy adult SD rat, male and female dual-purpose, random packet, fasting starts modeling, allows free water during animal fasting after 48 hours.Give control solvent, positive control drug and test-compound respectively according to experimental design.30min after administration, unless outside model group, through Indomethacin (dosage is 20mg/kg body weight) modeling is injected intraperitoneally.After modeling success, hemifumarate made from embodiment 1 is injected according to 1mg/kg, 3mg/kg and 9mg/kg respectively, gastric mucosa ulcer bleeding is calculated after 5 hours and is counted out and ulcer suppression percentage.As a result it is as follows：
The rat Indomethacin Ulceration model of table 2 -- suppress percentage (%)
Result of the test：The hemifumarate of the present invention can dose-dependently suppress gastric mucosa ulcer bleeding caused by Indomethacin, there is suppression trend under 1mg/kg dosage, 3mg/kg and 9mg/kg can substantially suppress ulcer bleeding (p is respectively smaller than 0.01 and 0.001), and inhibition is significantly stronger than 20mg/kg Omeprazole (p ＜ 0.05).
Experimental example 3, rat histamine stimulate the hydrochloric acid in gastric juice inhibitory action of model evaluation test-compound
Experiment purpose：
Evaluate hydrochloric acid in gastric juice inhibitory action of the test-compound (compound of embodiment 1) in rat histamine stimulates model.
Test method：
Give the test-compound of control solvent and various dose in particular point in time (4 hours before collection gastric juice) respectively according to experimental design.After administration 1 hour with ether by Animal Anesthesia, open abdominal cavity, ligature pylorus, histamine phosphate's solution is penetrated in Animal Skin bet (dosage is 30mg/kg).Injection histamine phosphate anesthetized animal after 3 hours, ligatures orifice of the stomach, collects gastric juice.
The experiment packet of table 3 and dosage
Testing index
The rat gastric juice of 1 hour to 4 hours after collection administration.A certain amount of hydrochloric acid in gastric juice sample is diluted to after detection volume, constant-current titration is carried out using NaOH titers (0.1036mol/L, 0.1006mol/L) with autotitrator, its acid content is determined, and total acid number is calculated according to population of samples product.
Acid output (mmol)=hydrochloric acid in gastric juice cumulative volume/titration stomach acid volume × consumption NaOH titers volume × NaOH concentration of standard solution
Gastric acid secretion inhibiting rate (I%)=[acid output (solvent group)-acid output (compound group)]/acid output (solvent group) × 100%
The rat histamine of table 4. stimulates model stomach acidimetric estimation (Mean ± SEM)
The rat histamine of table 5. stimulates model -- and hydrochloric acid in gastric juice and gastric juice suppress percentage (%)
Experimental result
Experimental result is as follows：4 hours after administration, compared with solvent group, test-compound (compound of embodiment 1) under various dose significantly (p is respectively smaller than 0.05 and 0.01) can reduce hydrochloric acid in gastric juice amount, and gastric acid secretion inhibiting rate can be respectively up to 62.4%, 90.3% and 99.7%.
The study on the stability of experimental example 4, crystal formation：
Carrying out 3 months accelerated stabilities to crystal formation 1 of the present invention (embodiment 1-1 is made), (setting-out condition is 40 DEG C ± 2 DEG C, the experiment investigation of RH75 ± 5%), sample is provided by Jiangsu Haosen Pharmaceutical Co., Ltd, the crystal formation product of three batches is respectively designated as VP-130401, VP-130402 and VP-130403,1~2 is see the table below with the initial X-ray powder diffraction data comparison of sample, relevant material stability is shown in Table 3.
The accelerated stability X-ray powder diffraction data comparison (- 2 θ) of table 1.
The accelerated stability X-ray powder diffraction data comparison (- d) of table 2.
The accelerated stability qualitative data of table 3. is contrasted
Above-mentioned 3 months accelerated stability as shown by data, crystal formation 1 has good stabilization.
Claims (18)
- 2- shown in a kind of formula (I) (3- ((2- (2- fluorophenyls) -4- ((methylamino) methyl) -1H- pyrroles -1- bases) sulfonyl) phenoxy group)-N- methylacetamide hemifumarates
- A kind of 2- (3- ((2- (2- fluorophenyls) -4- ((methylamino) methyl) -1H- pyrroles -1- bases) sulfonyl) phenoxy group)-N- methylacetamide hemifumarate crystal formations,There are its XRD spectrum characteristic peak (± 0.2 °) of 2 θ angles to be 7.858,9.456,13.202,14.836,15.099,15.749,15.050,19.948, preferably, also containing 2 θ angles, (± 0.2 °) is 19.901,20.922,22.423,24.867 characteristic peak, particularly preferred, the XRD spectrum of the crystal formation is as shown in Figure 3.
- The method for preparing crystal formation described in (3- ((2- (2- fluorophenyls) -4- ((methylamino) methyl) -1H- pyrroles -1- bases) sulfonyl) the phenoxy group)-N- methylacetamides hemifumarates of 2- shown in formula according to claim 1 (I) or claim 2; it is made including 2- (3- ((2- (2- fluorophenyls) -4- ((methylamino) methyl) -1H- pyrroles -1- bases) sulfonyl) the phenoxy group)-N- methylacetamides as shown in formula (II) and fumaric acid in organic solvent into salt crystallization
- Preparation method according to claim 3, comprises the following steps：1) formula (II) compound 2- (3- ((2- (2- fluorophenyls) -4- ((methylamino) methyl) -1H- pyrroles -1- bases) sulfonyl) phenoxy group)-N- methylacetamides are dissolved in organic solvent, add fumarate solid or fumaric acid solution；2) by above-mentioned reaction solution agitating and heating；3) cooling crystallization obtains formula (I) compound.
- Preparation method according to claim 3 or 4, it is characterised in that the organic solvent is alcohols solvent.
- Preparation method according to claim 5, it is characterised in that the alcohols solvent is selected from isopropanol or/and absolute ethyl alcohol, it is preferred that when alcohols solvent is isopropanol/absolute ethyl alcohol mixed solvent, wherein the ratio of isopropanol is 0.1%~100%.
- Preparation method according to claim 6, it is characterised in that the alcohols solvent is the mixed solvent system of isopropanol/absolute ethyl alcohol, and the volume ratio of isopropanol/absolute ethyl alcohol is 1~8: 1, preferably 3~5: 1, most preferably 4: 1.
- Preparation method according to claim 4, it is characterised in that the fumaric acid solution is the ethanol solution of fumaric acid.
- Preparation method according to claim 3 or 4, it is characterised in that the molar equivalent for adding fumaric acid is 0.4~0.5 equivalent of formula (II) compound, preferably 0.45~0.47 equivalent.
- Preparation method according to claim 4, it is characterised in that the step 2) temperature of agitating and heating is 50~82 DEG C, preferably reflux temperature.
- Pharmaceutical composition comprising 2- (3- ((2- (2- fluorophenyls) -4- ((methylamino) methyl) -1H- pyrroles -1- bases) sulfonyl) phenoxy group)-N- methylacetamides hemifumarates or its crystal formation and pharmaceutically acceptable carrier.
- Pharmaceutical composition according to claim 11, the existence form of said composition is tablet or capsule.
- (3- ((2- (2- fluorophenyls) -4- ((methylamino) methyl) -1H- pyrroles -1- bases) sulfonyl) the phenoxy group)-N- methylacetamides hemifumarates of 2- shown in formula (I) according to claim 1 or its crystal formation and claim 11 described pharmaceutical composition are preparing treatment gastroesophageal reflux; peptic ulcer; purposes in gastric ulcer, duodenal bulbar ulcer or esophagitis medicine.
- The intermediate for preparing 2- (3- ((2- (2- fluorophenyls) -4- ((methylamino) methyl) -1H- pyrroles -1- bases) sulfonyl) phenoxy group)-N- methylacetamide hemifumarates shown in formula (III)
- The method for preparing intermediate according to claim 14, including the tert-butyl group ((5- (2- fluorophenyls) -1H- pyrroles -3- bases) methyl) (methyl) carbonic ester is condensed in organic solvent with 3- (2- (methylamino) -2- oxoethoxies) phenyl -1- sulfonic acid chlorides obtained.
- Preparation method according to claim 14, it is characterised in that the organic solvent is selected from benzene,toluene,xylene, acetonitrile or DMF.
- The method for preparing the free alkali of intermediate according to claim 14, including the formula (III) compound is passed through hydrogen chloride gas, pH is adjusted to alkalescence with alkaline matter.
- Preparation method according to claim 17, it is characterised in that the alkaline matter is selected from sodium acid carbonate, sodium hydroxide or sodium carbonate.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2014106643940 | 2014-11-19 | ||
| CN2014106658838 | 2014-11-19 | ||
| CN201410664394.0A CN104447490B (en) | 2014-11-19 | 2014-11-19 | A kind of crystal formation of proton pump inhibitor, prepare intermediate and its synthetic method and medical usage |
| CN201410665883.8A CN104447491B (en) | 2014-11-19 | 2014-11-19 | Hemifumarate and its intermediate and medical usage containing pyrrole ring proton pump inhibitor |
| PCT/CN2015/094958 WO2016078594A1 (en) | 2014-11-19 | 2015-11-18 | Pyrrole ring-containing proton pump inhibitor being hemifumarate and crystal form thereof, intermediate and medical use thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN107001262A true CN107001262A (en) | 2017-08-01 |
Family
ID=56013302
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201580059766.XA Pending CN107001262A (en) | 2014-11-19 | 2015-11-18 | The hemifumarate and its crystal formation of the proton pump inhibitor containing pyrrole ring, intermediate and medical usage |
Country Status (3)
| Country | Link |
|---|---|
| CN (1) | CN107001262A (en) |
| TW (1) | TW201619129A (en) |
| WO (1) | WO2016078594A1 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111620804A (en) * | 2020-06-17 | 2020-09-04 | 山东理工大学 | Synthesis method and application of two sulfonyl pyrrolidine P-CABs |
| WO2023280288A1 (en) * | 2021-07-09 | 2023-01-12 | 天地恒一制药股份有限公司 | Pyrrole sulfonyl derivative, and preparation method therefor and application thereof |
| CN115594623A (en) * | 2021-07-09 | 2023-01-13 | 天地恒一制药股份有限公司（Cn） | Pyrrole sulfonyl derivative, and preparation method and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1803709A1 (en) * | 2004-09-30 | 2007-07-04 | Takeda Pharmaceutical Company Limited | Proton pump inhibitors |
| CN101300229A (en) * | 2005-08-30 | 2008-11-05 | 武田药品工业株式会社 | 1-heterocyclylsulfonyl, 2-aminomethyl, 5- (hetero-) aryl substituted 1-h-pyrrole derivatives as acid secretion inhibitors |
| WO2014075575A1 (en) * | 2012-11-19 | 2014-05-22 | 江苏豪森药业股份有限公司 | Pyrrole sulfonamide derivative, preparation method for same, and medical application thereof |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104447490B (en) * | 2014-11-19 | 2017-06-06 | 连云港恒运医药有限公司 | A kind of crystal formation of proton pump inhibitor, prepare intermediate and its synthetic method and medical usage |
| CN104447491B (en) * | 2014-11-19 | 2017-06-23 | 连云港恒运医药有限公司 | Hemifumarate and its intermediate and medical usage containing pyrrole ring proton pump inhibitor |
-
2015
- 2015-11-18 CN CN201580059766.XA patent/CN107001262A/en active Pending
- 2015-11-18 WO PCT/CN2015/094958 patent/WO2016078594A1/en active Application Filing
- 2015-11-19 TW TW104138403A patent/TW201619129A/en unknown
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1803709A1 (en) * | 2004-09-30 | 2007-07-04 | Takeda Pharmaceutical Company Limited | Proton pump inhibitors |
| CN101300229A (en) * | 2005-08-30 | 2008-11-05 | 武田药品工业株式会社 | 1-heterocyclylsulfonyl, 2-aminomethyl, 5- (hetero-) aryl substituted 1-h-pyrrole derivatives as acid secretion inhibitors |
| WO2014075575A1 (en) * | 2012-11-19 | 2014-05-22 | 江苏豪森药业股份有限公司 | Pyrrole sulfonamide derivative, preparation method for same, and medical application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| TW201619129A (en) | 2016-06-01 |
| WO2016078594A1 (en) | 2016-05-26 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104447491B (en) | Hemifumarate and its intermediate and medical usage containing pyrrole ring proton pump inhibitor | |
| KR100716389B1 (en) | N-Hydroxy??????????5?isopropyl???methyl??,??thiazol?4?yl?phenoxy?pentoxy?benzamidine ? methansulfonic acid salt | |
| CN101687848A (en) | Solid state forms of racemic ilaprazole | |
| CN102140092B (en) | Hydrate of ilaprazole salt, preparation method thereof and application thereof | |
| CN101553480B (en) | Helicobacter pylori eradicating agent having inhibitory activity on gastric acid secretion | |
| CN115304593B (en) | Benzisothiazole compound, and pharmaceutical composition and application thereof | |
| CN106957252B (en) | A kind of proton pump inhibitor intermediate and preparation method thereof | |
| CN107001262A (en) | The hemifumarate and its crystal formation of the proton pump inhibitor containing pyrrole ring, intermediate and medical usage | |
| CN102397277A (en) | Esomeprazole-containing medicinal composition | |
| CN102260244B (en) | Stable rabeprazole sodium compound | |
| CN102321072B (en) | Esomeprazole sodium hemihydrate | |
| JPH04217676A (en) | Carboxylic acid derivative | |
| JPS62207212A (en) | Antiallergic agent | |
| CN108969520A (en) | A kind of composition of the A crystal-form compound of N- methyl methylamine hydrochloride | |
| CN1705479B (en) | Use of distrontium 2-(n,n-di(carboxymethyl)amino)-3-cyano-4-carboxymethyl thiophene-5-carboxylate in preparing medicine to reduce gastro-duodenal pain | |
| CN101962388B (en) | Acetamide derivatives, preparation method and application thereof | |
| CN102336788B (en) | Glucosamine double salt for proton pump inhibitor | |
| KR101006254B1 (en) | N-Hydroxy-4-?5-?4-?5-isopropyl-2-methyl-1,3-thiazol-4-yl?phenoxy?pentoxy?benzamidine 2 ethansulfonic acid salt, process for the preparation thereof and pharmaceutical composition comprising the same | |
| CN110229141A (en) | A kind of novel preparation method of high-purity esomeprazole sodium | |
| CN116891443B (en) | Isoindol-1-one derivative and preparation method and application thereof | |
| CN102875566B (en) | Thiophene derivatives with anti-gastric ulcer effect | |
| CN103923033B (en) | There is the piperazine derivative of anti-ulcer effect | |
| CN101658530B (en) | Medicine combination for treating stomach and duodenum diseases | |
| AU2010235726B2 (en) | Pyridine thio derivative, and pharmaceutical composition which contains same and has anti-Helicobacter pylori action | |
| CN108524507A (en) | A kind of pharmaceutical composition for treating acute gastritis |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| CB03 | Change of inventor or designer information |
Inventor after: Zhong Chunhua Inventor after: Yu Jun Inventor after: Zhu Qiang Inventor after: Yang Baohai Inventor before: Yu Jun Inventor before: Zhu Qiang Inventor before: Yang Baohai |
|
| CB03 | Change of inventor or designer information | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20170801 |
|
| WD01 | Invention patent application deemed withdrawn after publication |