CN110642832A - Preparation method and application of lafutidine and intermediate thereof - Google Patents
Preparation method and application of lafutidine and intermediate thereof Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
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Abstract
The invention relates to a preparation method and application of lafutidine and an intermediate thereof, wherein the preparation method of lafutidine intermediate comprises the following steps:
Description
Technical Field
The invention belongs to the field of chemical pharmacy, and relates to a preparation method and application of lafutidine and an intermediate thereof.
Background
Lafutidine (Lafutidine) is a second-generation histamine H2 receptor antagonist with high and long-acting effects, and can inhibit gastric acid secretion caused by histamine, pentagastrin, etc., protect gastric mucosa, promote ulcer healing, relieve symptoms, and prevent recurrence of ulcer.
One key step in the preparation of lafutidine is the removal of the phthalyl protecting group in compound (I) of the formula below to produce a primary amine, key intermediate compound (II), followed by condensation to produce lafutidine:
EP282077a2 discloses the use of hydrazine hydrate to remove the phthalyl protecting group to effect the conversion of compound (I) to compound (II). The disadvantages of this method are: (1) hydrazine hydrate has potential safety hazards due to instability, high toxicity, easy volatilization and easy explosion; (2) the obtained crude lafutidine product has low purity, the main impurity is dihydrolafutidine (IV), and the reason for the generation is that the carbon-carbon double bond in the compound (I) is partially reduced to generate a compound (V) due to the reducibility of hydrazine hydrate while the phthalyl protecting group is removed; (3) the operation of removing the impurity dihydrolafutidine (IV) to purify the crude lafutidine product is complicated, and repeated recrystallization results in low yield and high cost;
JP07010816A discloses the removal of the phthaloyl protecting group using hydrazine hydrate under nitrogen protection to effect the conversion of compound (I) to compound (II). Although the protection of nitrogen improves the purity of the crude lafutidine product to a certain extent, the content of the main impurity dihydrolafutidine (IV) is still high, and hydrazine hydrate still has the potential safety hazard;
JP07010817A discloses that the conversion of compound (I) to compound (II) is effected by removing the phthaloyl protecting group with hydrazine hydrate in the presence of double bond-containing olefin compounds such as 1-hexene, 1-heptene, 1-octene, 1-nonene, 1-decene, 2(Z) -butene-1, 4-diol, 2(E) -butene-1, 4-diol. However, the inhibition of the main impurity dihydrolafutidine (IV) by the addition of the double bond-containing ene compound is still limited. Moreover, the addition of the double bond-containing olefin compound raises the raw material cost and the cost for treating three wastes, and the potential safety hazard of hydrazine hydrate cannot be completely avoided;
IN2009MU00749A discloses the removal of a phthaloyl protecting group using aqueous methylamine solution to effect the conversion of compound (I) to compound (II). In the method, a methylamine aqueous solution is used for replacing hydrazine hydrate, but methylamine is gaseous at normal temperature and normal pressure, and even though the methylamine aqueous solution is still extremely volatile to the atmosphere. Gaseous methylamine can be mixed with air to form an explosive mixture, and the explosive mixture can be combusted and exploded when exposed fire and high heat are encountered. Methylamine belongs to low toxicity, but still has irritation and corrosivity, and can cause pharyngolaryngitis, bronchitis, peribronchial inflammation and bronchopneumonia after being inhaled, and severe cases cause pulmonary edema to cause death; high concentration inhalation can cause death due to larynx spasm, respiratory tract burn, edema and asphyxia; it has strong irritation to eyes and skin, and can cause burn in severe cases. Therefore, the use of methylamine still has potential safety hazard;
IN2010MU00931A discloses the removal of the phthalyl protecting group using ethylenediamine to effect the conversion of compound (I) to compound (II). This method uses ethylenediamine instead of hydrazine hydrate, but: (1) the ethylenediamine meets open fire, high heat or contacts with an oxidant, so that the danger of combustion and explosion is caused, and potential safety hazard exists; (2) three wastes generated by using ethylenediamine are difficult to treat, so that water body pollution is caused, and the environment is seriously damaged;
CN103130782A discloses the use of hydroxylamine hydrochloride to remove the phthaloyl protecting group to effect the conversion of compound (I) to compound (II). However, hydroxylamine hydrochloride is extremely toxic, production equipment is sealed to prevent leakage, overflow, dripping and leakage, and operators wear protective tools to ensure life and environmental safety.
Therefore, the development of a preparation method of the lafutidine intermediate (II) suitable for large-scale production and a preparation method of lafutidine with improved impurity content, which can effectively improve the above defects of the prior art, is urgently needed.
Disclosure of Invention
The invention aims to provide a preparation method of a lafutidine intermediate shown as a formula (II), which comprises the following steps:
wherein the compound of formula (I) is reacted in the presence of an organic base of the alcamines type and at least one other basic compound to give a compound of formula (II).
According to the invention, the organic alcamines, designated OB, can be chosen from one, two or more compounds of the alcolamines, which are basic, for example a compound of formula
N(A)m(B)n
Wherein A and B are each bonded to an N atom;
each A, which may be the same or different, is independently selected from the group consisting of: H. alkyl, cycloalkyl, heterocyclic radicals, e.g. C1-40Alkyl radical, C3-20Cycloalkyl, 3-20 membered heterocyclyl;
each B, which may be the same or different, is independently selected from the following groups: hydroxyalkyl, hydroxycycloalkyl, hydroxyheterocyclyl, e.g. hydroxy C1-40Alkyl, hydroxy C3-20Cycloalkyl, hydroxy 3-20 membered heterocyclyl;
m is selected from 0, 1,2 or 3;
n＝3-m。
as an example, the organic base of the alcamines may be selected from one, two or more of the following: monoethanolamine (also known as ethanolamine), diethanolamine, triethanolamine, 3-propanolamine, monoisopropanolamine (also known as isopropanolamine), diisopropanolamine, triisopropanolamine, N-dimethylethanolamine, N-diethylethanolamine.
The at least one further basic compound, designated IB, means at least one of an organic or inorganic base other than an organic base of the alcamines, preferably one, two or more selected from the following: sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, methylamine, ethylamine, propylamine, isopropylamine, dimethylamine, diethylamine, diisopropylamine, triethylamine.
Preferably, the compound of formula (I) is reacted first with OB and then with IB.
According to an embodiment of the invention, the molar ratio of the compound of formula (I) to OB may be 1 (1-20), such as 1 (5-15), e.g. 1 (6-14), e.g. 1: 10.
According to an embodiment of the invention, the molar ratio of the compound of formula (I) to IB may be 1 (1-10), such as 1 (2-8), e.g. 1 (3-7), such as 1 (4-6), e.g. 1: 5.
According to an embodiment of the invention, the reaction may optionally be carried out in the presence or absence of a solvent.
According to an exemplary embodiment of the present invention, the preparation method comprises the steps of:
1) reacting a compound of formula (I) with OB in the presence of a solvent;
2) adding IB into the mixture obtained in the step 1) and reacting.
According to an embodiment of the invention, in step 1):
the solvent may be an organic solvent (designated S1), for example an alcoholic solvent, such as one, two or more selected from the group consisting of: methanol, ethanol, propanol, isopropanol, butanol, 2-butanol, tert-butanol, for example methanol, ethanol or mixtures thereof;
the reaction time may be from 0.5 to 12 hours, for example from 1 to 6 hours, such as from 2 to 5 hours, for example 3.5 hours;
the reaction temperature may be from-5 ℃ to 40 ℃, e.g. from 0 ℃ to 35 ℃, such as from 20 ℃ to 30 ℃;
in step 2):
IB may be added in the form of an aqueous solution thereof, which may have a concentration of 1% to 50% by mass, for example 2% to 40%, 3% to 30%, 4% to 20%, 5% to 15%, such as 8% to 12%, such as 10%;
the reaction time may be from 0.5 to 12 hours, for example from 1 to 6 hours, such as from 2 to 5 hours, for example 3.5 hours;
the reaction temperature may be from-5 ℃ to 40 ℃, for example from 0 ℃ to 35 ℃, such as from 15 ℃ to 35 ℃, such as from 20 ℃ to 30 ℃.
Preferably, after step 2), the organic solvent is distilled off, the good solvent for the compound of formula (II) (named S2) is added, the organic phase is washed with water and/or brine (e.g. brine), dried and filtered to obtain a solution of the compound of formula (II) in the solvent S2.
Optionally, after addition of solvent S2, water is also added.
Preferably, the solvent S2 is an organic solvent, such as an aromatic hydrocarbon solvent, a halogenated hydrocarbon solvent, an ether solvent, an ester solvent, such as one, two or more selected from the group consisting of: benzene, toluene, xylene, dichloromethane, 1, 2-dichloroethane, ethylene glycol dimethyl ether, 1, 4-dioxane, isopropyl ether, tert-butyl methyl ether, ethyl formate, propyl formate, butyl formate, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate.
According to embodiments of the invention, the weight to volume ratio of the compound of formula (I) to solvent S2 may be 1g (1-10) mL, such as 1g:6 mL; when water is further added after the addition of solvent S2, the weight to volume ratio of the compound of formula (I) to water may be 1g (2-6) mL, such as 1g:4 mL.
According to an embodiment of the present invention, the evaporation of the organic solvent may be performed under reduced pressure, and the temperature may be 20 ℃ to 70 ℃, for example, 40 ℃ to 50 ℃;
illustratively, when the organic phase is washed with water, the weight to volume ratio of the compound of formula (I) to the wash water may be 1g (2-6) mL, such as 1g:4 mL; when the organic phase is washed with brine, the weight to volume ratio of the compound of formula (I) to the wash brine may be 1g (1-5) mL, such as 1g:3 mL;
illustratively, the saline may be present at a concentration of 1% to 10%, such as 3% to 6%, for example 5% by weight.
Illustratively, the drying is performed using a desiccant. For example, the drying agent may be selected from one, two or more of anhydrous sodium sulfate, anhydrous magnesium sulfate, anhydrous calcium chloride, anhydrous magnesium chloride, and the like.
The invention also provides a preparation method of lafutidine, which comprises the preparation method of lafutidine intermediate shown in formula (II).
According to an embodiment of the present invention, the preparation method of lafutidine comprises:
a) obtaining a compound shown in a formula (II) according to the preparation method of the lafutidine intermediate shown in the formula (II);
b) preparing lafutidine using the compound of formula (II) obtained in step a).
According to an exemplary embodiment, step b) is carried out by:
according to the invention, the compound of formula (II) can be subjected to a condensation reaction with the compound of formula (VI) to obtain lafutidine.
Wherein R can be any one of o-nitrophenyl, p-nitrophenyl or 2, 4-dinitrophenyl.
Preferably, after step a), a solution of the compound of formula (II) in the solvent S2 is obtained and subjected to a condensation reaction with the compound of formula (VI) without further purification.
According to the embodiment of the invention, the mass ratio of the compound of formula (VI) to the compound of formula (I) is 1 (1-3), and for example, may be 1: 1.64.
According to an embodiment of the present invention, the condensation reaction may optionally be added or not added with other solvents other than solvent S2, which are organic solvents, such as aromatic hydrocarbon solvents, halogenated hydrocarbon solvents, ether solvents, ester solvents or other solvents, such as one, two or more selected from the following: benzene, toluene, dichloromethane, chloroform, carbon tetrachloride, diethyl ether, dimethyl ether, 1, 4-dioxane, isopropyl ether, tert-butyl methyl ether, ethyl formate, propyl formate, butyl formate, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, tetrahydrofuran, N-dimethylformamide, acetonitrile.
According to embodiments of the invention, the reaction temperature of the condensation reaction may be from 0 ℃ to 50 ℃, e.g., from 35 ℃ to 40 ℃; the reaction time can be 3-6 h, for example 5 h.
Preferably, after the condensation reaction is completed, the obtained mixture is placed at a certain temperature, washed once or more than twice by using an alkali solution and brine (such as saline), dried, filtered, the volatile matters in the filtrate are removed by reduced pressure evaporation, and the residue is recrystallized to obtain the lafutidine.
According to an embodiment of the invention, the certain temperature may be 10 ℃ to 35 ℃, such as 20 ℃ to 30 ℃.
According to an embodiment of the invention, the alkali solution is an aqueous solution of one, two or more of the following inorganic bases: sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium bicarbonate.
Illustratively, the alkali solution may be present in a concentration of 1% to 20% by mass, such as 2% to 15%, for example 5%.
Illustratively, the saline may be present at a concentration of 1% to 10%, such as 3% to 6%, for example 5% by weight.
Optionally, after washing with an alkaline solution, water may also be added for washing, followed by washing with brine (e.g., saline).
According to an embodiment of the invention, the weight to volume ratio of the compound of formula (I) to the base solution, saline, may be 1g (1-10) mL, such as 1g:2mL:2mL, per wash; when water is also added after the addition of the base solution, the weight to volume ratio of the compound of formula (I) to water may be 1g (1-3) mL, such as 1g:2 mL.
Illustratively, the drying is performed using a desiccant. For example, the drying agent may be selected from one, two or more of anhydrous sodium sulfate, anhydrous magnesium sulfate, anhydrous calcium chloride, anhydrous magnesium chloride, and the like.
According to an embodiment of the invention, the evaporation of volatiles may be carried out under reduced pressure and the temperature may be from 20 ℃ to 70 ℃, for example from 40 ℃ to 50 ℃.
According to an embodiment of the invention, the recrystallization comprises the steps of: adding a recrystallization solvent, heating and stirring for a period of time, slowly cooling to room temperature, continuing stirring at a low temperature, filtering and drying a filter cake to obtain the lafutidine.
According to an embodiment of the invention, the recrystallization solvent is selected from one, two or more of the following: dimethyl ether, ethylene glycol dimethyl ether, isopropyl ether, tert-butyl methyl ether, ethyl formate, propyl formate, butyl formate, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate.
According to an embodiment of the present invention, the weight to volume ratio of the compound of formula (I) to the recrystallization solvent may be 1g (1-3) mL, such as 1g:1 mL.
Illustratively, the temperature rise can be raised to 50 ℃ to 80 ℃, for example, the temperature rise can be raised to 60 ℃ to 70 ℃;
the time for heating and stirring can be 10-120 min, for example, 30 min;
the low temperature may be from-5 ℃ to 15 ℃, for example, from 0 ℃ to 10 ℃;
the stirring time at low temperature may be 10 to 120min, for example, 30 min.
According to an embodiment of the invention, the drying may be performed under vacuum, and the drying temperature may be 30 ℃ to 50 ℃, for example, may be 40 ℃ to 45 ℃; the drying time may be 6 to 16 hours, for example, 10 hours.
The present invention also provides a mixture comprising a compound of formula (I) as described above and OB.
According to an embodiment of the present invention, the mixture may further comprise IB as described above.
According to an embodiment of the present invention, the mixture may further comprise the above-mentioned organic solvent and water.
The invention also provides the application of the mixture in preparing the compound of the formula (II) or lafutidine.
The invention also provides the use of a composition for the preparation of a compound of formula (II) or lafutidine, wherein the composition comprises the organic base of the alcamines and the at least one further basic compound.
The chemical names of the compounds (I) to (V) and lafutidine are as follows:
compound (I): 2- [4- (4-piperidin-1-ylmethyl-pyridin-2-yloxy) -2(Z) -butenyl ] -isoindole-1.3-dione maleate;
compound (II): 4- (4-piperidin-1-ylmethyl-pyridin-2-yloxy-2 (Z) -butenamine;
compound (III): 2- (2-furylmethyl sulfinyl) -acetic acid-4-nitrophenyl ester;
compound (IV): 2- (2-furylmethyl sulfinyl) -N- [4- [4- (1-piperidinylmethyl) -2-pyridinyl ] oxybutyl ] acetamide;
compound (V): 4- [4- (1-piperidinylmethyl) -2-pyridinyloxy ] butylamine;
lafutidine: 2- (2-Furanylmethyl sulfinyl) -N- [4- [4- (1-piperidinylmethyl) -2-pyridyl ] oxy-2 (Z) -butenyl ] acetamide.
Definition and description of terms
Unless otherwise indicated, the definitions of groups and terms described in the specification and claims of the present application, including definitions thereof as examples, exemplary definitions, preferred definitions, definitions described in tables, definitions of specific compounds in the examples, and the like, may be arbitrarily combined and coupled with each other. The definitions of the groups and the structures of the compounds in such combinations and after the combination are within the scope of the present specification.
The term "C1-40Alkyl "is understood to mean a straight-chain or branched, saturated monovalent hydrocarbon radical having from 1 to 40 carbon atoms, preferably C1-10An alkyl group. "C1-10Alkyl "is understood to mean a straight-chain or branched, saturated monovalent hydrocarbon radical having 1,2, 3,4, 5,6, 7, 8, 9 or 10 carbon atoms. The alkyl group is, for example, methyl, ethyl,Propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-ethylpropyl, 1, 2-dimethylpropyl, neopentyl, 1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 2, 3-dimethylbutyl, 1, 3-dimethylbutyl, or 1, 2-dimethylbutyl, and the like or isomers thereof. In particular, the radicals have 1,2, 3,4, 5,6 carbon atoms ("C)1-6Alkyl groups) such as methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, tert-butyl, more particularly groups having 1,2 or 3 carbon atoms ("C)1-3Alkyl groups) such as methyl, ethyl, n-propyl or isopropyl.
The term "C3-20Cycloalkyl is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 20 carbon atoms, preferably "C3-10Cycloalkyl groups ". The term "C3-10Cycloalkyl "is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3,4, 5,6, 7, 8, 9 or 10 carbon atoms. Said C is3-10Cycloalkyl groups may be monocyclic hydrocarbon groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or bicyclic hydrocarbon groups such as decalin rings.
The term "C1-40Alkoxy "is to be understood as meaning C1-40Alkoxy radical, wherein C1-40Alkyl groups have the definitions described above.
The term "3-20 membered heterocyclyl" means a saturated monovalent monocyclic or bicyclic hydrocarbon ring comprising 1-5 heteroatoms independently selected from N, O and S, preferably "3-10 membered heterocyclyl". The term "3-10 membered heterocyclyl" means a saturated or unsaturated monovalent monocyclic or bicyclic hydrocarbon ring comprising 1-5, preferably 1-3 heteroatoms selected from N, O and S. The heterocyclic group may be attached to the rest of the molecule through any of the carbon atoms or nitrogen atom (if present). In particular, the heterocyclic group may include, but is not limited to: 4-membered rings such as azetidinyl, oxetanyl; 5-membered rings such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or a 6-membered ring such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl; or a 7-membered ring such as diazepanyl. Optionally, the heterocyclic group may be benzo-fused. The heterocyclyl group may be bicyclic, for example but not limited to a 5,5 membered ring, such as a hexahydrocyclopenta [ c ] pyrrol-2 (1H) -yl ring, or a 5,6 membered bicyclic ring, such as a hexahydropyrrolo [1,2-a ] pyrazin-2 (1H) -yl ring. The nitrogen atom containing ring may be partially unsaturated, i.e., it may contain one or more double bonds, such as, but not limited to, 2, 5-dihydro-1H-pyrrolyl, 4H- [1,3,4] thiadiazinyl, 4, 5-dihydrooxazolyl, or 4H- [1,4] thiazinyl, or it may be benzo-fused, such as, but not limited to, dihydroisoquinolinyl. According to the invention, the heterocyclic radical is non-aromatic.
Unless otherwise indicated, when the present invention relates to percentages between liquids, said percentages are volume/volume percentages; the invention relates to the percentage between liquid and solid, said percentage being volume/weight percentage; the invention relates to the percentages between solid and liquid, said percentages being weight/volume percentages; the balance being weight/weight percent.
The invention has the advantages of
1) The preparation method of the lafutidine intermediate disclosed by the invention avoids the following defects:
a) due to the use of hydrazine hydrate (unstable, extremely toxic, volatile and explosive), a byproduct (dihydrolafutidine which is difficult to remove) is generated and potential safety production hazards are caused;
b) because of the use of methylamine water solution (low boiling point, volatile; the gaseous methylamine and air can be mixed to form an explosive mixture, and the explosive mixture can be combusted and exploded due to the exposure to open fire and high heat; after inhalation, pharyngolaryngitis, bronchitis, peribronchitis and bronchopneumonia can be caused, and pulmonary edema can be caused in serious cases to die; high concentration inhalation can cause larynx spasm, respiratory tract burn, edema and asphyxia to death; strong irritation to eyes and skin, serious burn can be caused);
c) the use of ethylenediamine (which is exposed to open flame, high heat or contact with oxidizing agents, poses the risk of causing combustion and explosion; three wastes are difficult to treat, causing water body pollution) to cause potential safety production hazards and harm to the environment;
d) the potential safety production hazard caused by using hydroxylamine hydrochloride (which is extremely toxic and can prevent running, overflowing, dripping and leaking) is avoided;
2) stable quality and high purity: the lafutidine intermediate obtained by the preparation method provided by the invention can be directly used for condensation reaction to prepare lafutidine without purification, the product lafutidine has few impurity types, the total impurities are lower than 0.15%, and dihydrolafutidine is not detected;
3) high yield and low cost: the lafutidine and the intermediate thereof obtained by the preparation method provided by the invention have high purity, so that the complicated purification operation is avoided, the product yield is improved, and the cost is reduced.
Detailed description of the preferred embodiments
The preparation and use of the present invention will be described in further detail with reference to specific examples. It is to be understood that the following examples are only illustrative and explanatory of the present invention and should not be construed as limiting the scope of the present invention. All the technologies realized based on the above-mentioned contents of the present invention are covered in the protection scope of the present invention.
The experimental methods used in the following examples are all conventional methods unless otherwise specified; reagents, materials and the like used in the following examples are commercially available unless otherwise specified.
Example 1
Preparation of lafutidine
1) Suspending 100 g of compound (I) in 500 ml of ethanol at 20-30 ℃ under stirring, controlling the temperature to be 0-5 ℃, adding 120 g of ethanolamine, controlling the temperature to be 25-30 ℃, stirring for 3.5 hours, adding 400 g of 10% sodium hydroxide aqueous solution, and continuously stirring for 3.5 hours at 25-30 ℃;
2) and (3) evaporating the reaction mixture at 40-50 ℃ under reduced pressure to remove volatile matters, adding 600 ml of ethyl acetate and 400 ml of water, stirring at 20-30 ℃ for 30 minutes, and standing for layering. Washing the organic layer with 400 ml of water and 300 ml of 5% saline solution in sequence, drying the organic layer with anhydrous sodium sulfate, and filtering the organic layer to obtain an ethyl acetate solution of the key intermediate compound (II);
3) transferring the ethyl acetate solution to a reaction bottle, adding 61 g of the compound (III), and stirring at 35-40 ℃ for 5 hours. Washing the reaction mixture with 200 ml of 5% sodium hydroxide solution (twice), 200 ml of water and 200 ml of 5% saline water at 20-30 ℃, drying with anhydrous sodium sulfate and filtering;
4) evaporating the filtrate at 40-50 ℃ under reduced pressure to remove volatile matters, adding 100 ml of isopropyl ether, stirring at 60-70 ℃ for 30 minutes, slowly cooling to room temperature, stirring at 5-10 ℃ for half an hour, and filtering;
5) vacuum drying the filter cake at 40-45 ℃ for 10 hours to obtain 73 g of lafutidine; the yield is 86%; the purity is 99.96 percent; total impurities 0.04%, dihydrolafutidine not detected.
Example 2
Preparation of lafutidine
1) Suspending 100 g of compound (I) in 500 ml of methanol at 20-30 ℃ under stirring, controlling the temperature to be 0-5 ℃, adding 120 g of ethanolamine, controlling the temperature to be 25-30 ℃, stirring for 3.5 hours, adding 400 g of 10% sodium hydroxide aqueous solution, and continuously stirring for 3.5 hours at 25-30 ℃;
2) and (3) evaporating the reaction mixture at 40-50 ℃ under reduced pressure to remove volatile matters, adding 600 ml of ethyl acetate and 400 ml of water, stirring at 20-30 ℃ for 30 minutes, and standing for layering. Washing the organic layer with 400 ml of water and 300 ml of 5% saline solution in sequence, drying the organic layer with anhydrous sodium sulfate, and filtering the organic layer to obtain an ethyl acetate solution of the key intermediate compound (II);
3) transferring the ethyl acetate solution to a reaction bottle, adding 61 g of the compound (III), and stirring at 35-40 ℃ for 5 hours. Washing the reaction mixture with 200 ml of 5% sodium hydroxide solution (twice), 200 ml of water and 200 ml of 5% saline water at 20-30 ℃, drying with anhydrous sodium sulfate and filtering;
4) evaporating the filtrate at 40-50 ℃ under reduced pressure to remove volatile matters, adding 100 ml of isopropyl ether, stirring at 60-70 ℃ for 30 minutes, slowly cooling to room temperature, stirring at 5-10 ℃ for half an hour, and filtering;
5) vacuum drying the filter cake at 40-45 ℃ for 10 hours to obtain 73 g of lafutidine; the yield is 86%; the purity is 99.92%; total impurities 0.08%, dihydrolafutidine was not detected.
Example 3
Preparation of lafutidine
1) Suspending 100 g of compound (I) in 500 ml of ethanol at 20-30 ℃ under stirring, controlling the temperature to be 0-5 ℃, adding 120 g of ethanolamine, controlling the temperature to be 25-30 ℃, stirring for 3.5 hours, adding 400 g of 10% sodium hydroxide aqueous solution, and continuously stirring for 3.5 hours at 25-30 ℃;
2) and (3) evaporating the reaction mixture at 40-50 ℃ under reduced pressure to remove volatile matters, adding 600 ml of isopropyl acetate and 400 ml of water, stirring at 20-30 ℃ for 30 minutes, and standing for layering. Washing the organic layer with 400 ml of water and 300 ml of 5% sodium chloride solution in sequence, drying the organic layer with anhydrous sodium sulfate, and filtering the organic layer to obtain an isopropyl acetate solution of the key intermediate compound (II);
3) transferring the isopropyl acetate solution to a reaction bottle, adding 61 g of the compound (III), and stirring at 35-40 ℃ for 5 hours. Washing the reaction mixture with 200 ml of 5% sodium hydroxide solution (twice), 200 ml of water and 200 ml of 5% saline solution at 20-30 ℃, drying with anhydrous sodium sulfate and filtering;
4) evaporating the filtrate at 40-50 ℃ under reduced pressure to remove volatile matters, adding 100 ml of isopropyl ether, stirring at 60-70 ℃ for 30 minutes, slowly cooling to room temperature, stirring at 5-10 ℃ for half an hour, and filtering;
5) vacuum drying the filter cake at 40-45 ℃ for 10 hours to obtain 74 g of lafutidine; the yield is 87%; the purity is 99.86 percent; total impurities 0.14%, dihydrolafutidine was not detected.
Example 4
Preparation of lafutidine
1) Suspending 100 g of compound (I) in 500 ml of methanol at 20-30 ℃ under stirring, controlling the temperature to be 0-5 ℃, adding 120 g of ethanolamine, controlling the temperature to be 25-30 ℃, stirring for 3.5 hours, adding 400 g of 10% sodium hydroxide aqueous solution, and continuously stirring for 3.5 hours at 25-30 ℃;
2) and (3) evaporating the reaction mixture at 40-50 ℃ under reduced pressure to remove volatile matters, adding 600 ml of isopropyl acetate and 400 ml of water, stirring at 20-30 ℃ for 30 minutes, and standing for layering. Washing the organic layer with 400 ml of water and 300 ml of 5% sodium chloride solution in sequence, drying the organic layer with anhydrous sodium sulfate, and filtering the organic layer to obtain an isopropyl acetate solution of the key intermediate compound (II);
3) transferring the isopropyl acetate solution to a reaction bottle, adding 61 g of the compound (III), and stirring at 35-40 ℃ for 5 hours. Washing the reaction mixture with 200 ml of 5% sodium hydroxide solution (twice), 200 ml of water and 200 ml of 5% saline water at 20-30 ℃, drying with anhydrous sodium sulfate and filtering;
4) evaporating the filtrate at 40-50 ℃ under reduced pressure to remove volatile matters, adding 100 ml of isopropyl ether, stirring at 60-70 ℃ for 30 minutes, slowly cooling to room temperature, stirring at 5-10 ℃ for half an hour, and filtering;
5) vacuum drying the filter cake at 40-45 ℃ for 10 hours to obtain 73 g of lafutidine; the yield is 86%; the purity is 99.94%; total impurities 0.06%, dihydrolafutidine was not detected.
The embodiments of the present invention have been explained above. However, the present invention is not limited to the above embodiment. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A preparation method of a lafutidine intermediate shown as a formula (II) comprises the following steps:
wherein the compound of formula (I) is reacted in the presence of an organic base of the alcamines type and at least one other basic compound to give a compound of formula (II).
2. The process according to claim 1, wherein the organic alcamines are named OB and can be chosen from one, two or more basic alcolamines, such as formula N (A)m(B)nAs shown in the drawings, the above-described,
wherein A and B are each bonded to an N atom;
each A, which may be the same or different, is independently selected from the group consisting of: H. alkyl, cycloalkyl, heterocyclic radicals, e.g. C1-40Alkyl radical, C3-20Cycloalkyl, 3-20 membered heterocyclyl;
each B, which may be the same or different, is independently selected from the following groups: hydroxyalkyl, hydroxycycloalkyl, hydroxyheterocyclyl, e.g. hydroxy C1-40Alkyl, hydroxy C3-20Cycloalkyl, hydroxy 3-20 membered heterocyclyl;
m is selected from 0, 1,2 or 3;
n＝3-m。
3. the process according to claim 1 or 2, characterized in that the organic base of the alcamines can be chosen from one, two or more of the following: monoethanolamine, diethanolamine, triethanolamine, 3-propanolamine, monoisopropanolamine, diisopropanolamine, triisopropanolamine, N-dimethylethanolamine, N-diethylethanolamine.
4. The preparation process according to any one of claims 1 to 3, characterized in that the at least one other basic compound, designated IB, means at least one of an organic or inorganic base other than an organic base of the alcamines type, preferably selected from one, two or more of the following: sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide.
5. The process according to any one of claims 1 to 4, wherein the molar ratio of the compound of formula (I) to OB is 1 (1 to 20) and the molar ratio of the compound of formula (I) to IB is 1 (1 to 10).
6. A process for the preparation of lafutidine comprising the process of any one of claims 1 to 5, comprising the steps of:
a) obtaining a compound shown in a formula (II) according to the preparation method of the lafutidine intermediate shown in the formula (II);
b) preparing lafutidine using the compound of formula (II) obtained in step a).
7. A mixture comprising a compound of formula (I) according to any one of claims 1 to 6 and OB.
8. The mixture of claim 7, wherein the mixture further comprises IB.
9. Use of a mixture according to claim 7 or 8 for the preparation of a compound of formula (II) or lafutidine.
10. Use of a composition for the preparation of a compound of formula (II) or lafutidine:
wherein the composition comprises OB and IB;
wherein OB is selected from the group consisting of alkanolamine organic bases, which may be selected from one, two or more of the alkylalkylamine compounds that are basic, which may be of formula N (A)m(B)nAs shown in the drawings, the above-described,
wherein A and B are each bonded to an N atom;
each A, which may be the same or different, is independently selected from the group consisting of: H. alkyl, cycloalkyl, heterocyclic radicals, e.g. C1-40Alkyl radical, C3-20Cycloalkyl, 3-20 membered heterocyclyl;
each B, which may be the same or different, is independently selected from the following groups: hydroxyalkyl, hydroxycycloalkylHydroxyheterocyclic radicals, e.g. hydroxy C1-40Alkyl, hydroxy C3-20Cycloalkyl, hydroxy 3-20 membered heterocyclyl;
m is selected from 0, 1,2 or 3;
n＝3-m；
IB is selected from at least one of organic bases or inorganic bases other than the above-mentioned organic bases of the alkanolamines, preferably one, two or more selected from the following: sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, methylamine, ethylamine, propylamine, isopropylamine, dimethylamine, diethylamine, diisopropylamine, triethylamine.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0282077A2 (en) * | 1987-03-13 | 1988-09-14 | Fujirebio Kabushiki Kaisha | Pyridyloxy derivatives |
| JPH0770072A (en) * | 1993-06-30 | 1995-03-14 | Sankyo Co Ltd | Thiourea derivative |
| CN102212060A (en) * | 2010-12-31 | 2011-10-12 | 北京双鹤药业股份有限公司 | Method for preparing lafutidine by virtue of aminolysis |
| CN102276588A (en) * | 2011-05-05 | 2011-12-14 | 四川科伦药物研究有限公司 | Novel technology for preparing lafutidine |
| CN103130782A (en) * | 2013-03-22 | 2013-06-05 | 北京国联诚辉医药技术有限公司 | Method for preparing lafutidine from hydroxylamine hydrochloride |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0282077A2 (en) * | 1987-03-13 | 1988-09-14 | Fujirebio Kabushiki Kaisha | Pyridyloxy derivatives |
| JPH0770072A (en) * | 1993-06-30 | 1995-03-14 | Sankyo Co Ltd | Thiourea derivative |
| CN102212060A (en) * | 2010-12-31 | 2011-10-12 | 北京双鹤药业股份有限公司 | Method for preparing lafutidine by virtue of aminolysis |
| CN102276588A (en) * | 2011-05-05 | 2011-12-14 | 四川科伦药物研究有限公司 | Novel technology for preparing lafutidine |
| CN103130782A (en) * | 2013-03-22 | 2013-06-05 | 北京国联诚辉医药技术有限公司 | Method for preparing lafutidine from hydroxylamine hydrochloride |
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