WO2018018851A1 - 奥司他韦羧酸盐酸盐及其雾化剂的制备方法 - Google Patents

奥司他韦羧酸盐酸盐及其雾化剂的制备方法 Download PDF

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WO2018018851A1
WO2018018851A1 PCT/CN2017/000426 CN2017000426W WO2018018851A1 WO 2018018851 A1 WO2018018851 A1 WO 2018018851A1 CN 2017000426 W CN2017000426 W CN 2017000426W WO 2018018851 A1 WO2018018851 A1 WO 2018018851A1
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solution
compound
preparation
oseltamivir
carboxylate hydrochloride
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PCT/CN2017/000426
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French (fr)
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邬征
彭程
许庆
吴陈亮
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上海爱科百发生物医药技术有限公司
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    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/52—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention belongs to the field of drug synthesis and preparation, and particularly relates to the preparation of an anti-influenza medicine, in particular to a preparation method of oseltamivir carboxylate hydrochloride and an atomizing agent thereof.
  • the flu virus is a virus that causes influenza in humans and animals.
  • the flu virus belongs to the Orthomyxoviridae family, which causes acute upper respiratory tract infections and is rapidly spread by air, often in the world.
  • a cyclical pandemic According to the antigenicity of influenza virus nucleoprotein, it can be divided into three types: A, B and C. Among them, type A and type B are prone to cause influenza pandemic, while type C appears in scattered form and generally does not cause epidemics.
  • the influenza virus is a negative-strand RNA virus that is spherical (80-120 nm in diameter) and contains a segmental genome.
  • Influenza A and B viruses contain 8 RNA segments, each of which is enveloped by viral nucleoprotein and associated by a polymerase complex.
  • the complex particles formed by nuclear proteins, RNA and polymerase, called ribonucleoprotein particles, are encapsulated by a lipid membrane composed of matrix protein M1 and membrane protein M2.
  • Two spike proteins are embedded in the lipid membrane and extend to the surface of the virus: rod-shaped hemagglutinin and mushroom-like neuraminidase, respectively. These two classes of proteins play an important role in the replication of the virus.
  • the flu is a highly contagious disease that is mainly transmitted by human respiratory secretions.
  • flu infections are spread by droplets produced by coughing or sneezing. The infection is usually thought to start from the tracheal bronchial epithelial tissue and then spread. Histological studies have shown that influenza virus replication occurs throughout the upper and lower respiratory tract. The onset of influenza disease is closely related to the progress of viral replication.
  • influenza virus replicates in the respiratory tract, it affects the state of the whole body. Infection and replication of the flu virus can cause death of the host cell, which can lead to inflammation of the respiratory tract and trigger a rapid immune response, leading to systemic symptoms including malaise, fever, chills, headache, loss of appetite, muscle aches and dizziness. .
  • systemic symptoms include malaise, fever, chills, headache, loss of appetite, muscle aches and dizziness.
  • These early systemic symptoms are usually accompanied by respiratory symptoms such as dry cough, runny nose, sneezing, and sore throat.
  • Low frequency Symptoms include a coughing sputum, hoarseness, and pain in the back of the chest. Systemic symptoms usually last 3-4 days, but cough and physical discomfort may persist for 2 weeks after the fever has subsided. After being infected with the flu, it is also easy to induce serious complications, such as complicated pneumonia, myocarditis, meningitis and other serious diseases, and even cause death.
  • a global influenza pandemic will occur due to the emergence of new influenza virus antigens. And because people have little or no immunity against new viruses, a pandemic can affect 50% of the world's population. There have been hundreds of years of reports on the global influenza pandemic. The well-documented influenza pandemic occurred in 1918 (Spanish flu), 1957 (Asian flu) and 1968 (Hong Kong flu), causing 30 million, 1 million and 800,000 deaths. In 2009, H1N1 swine flu spread to more than 200 countries and regions around the world, killing 20,000 people.
  • influenza There are two main methods for controlling influenza: 1) prevention, vaccination or other antiviral prophylactic drugs; 2) treatment with antiviral drugs.
  • the latter approach is intended to alleviate symptoms after viral infection and to shorten the duration of infection while preventing other complications such as bronchitis and pneumonia.
  • High-risk groups generally recommend vaccination to prevent infections, such as the elderly, children, patients with severe chronic diseases, low immunity, and people who may be in close contact with patients. Because the high variability of influenza viruses increases the difficulty of responding to influenza, people cannot accurately predict the prevalence of viral subtypes, and they cannot be targeted for preventive vaccination. On the other hand, antigenic changes that occur every few decades produce new strains of influenza that are completely devoid of vaccines.
  • the M2 inhibitors amantadine and rimantadine were discovered in the 1960s and were marketed in the 1980s for the treatment of influenza. Both drugs are three-membered ring-substituted primary amines containing 10 carbons.
  • the M2 ion channel plays an important role in the shelling replication of the virus after it enters the host cell. These two drugs exert an antiviral effect by inhibiting the M2 ion channel. Since the M2 protein is only expressed in influenza A, the M2 inhibitor has no therapeutic effect on influenza B. These two drugs can cause significant gastrointestinal side effects. At the same time, amantadine also has an adverse effect on the central nervous system.
  • influenza virus strains have developed resistance to this class of drugs in the clinic, limiting the class of drugs. The use of substances in the treatment of influenza.
  • Neuraminidase is a glycoside hydrolase that is expressed in both influenza A and B viruses.
  • the hemagglutinin on the surface of the virus will remain in contact with the host cell membrane via the sialic acid receptor, and the sialic acid needs to be hydrolyzed by neuraminidase to cleave the virus and the host cell.
  • the amino acid sequence of the neuraminidase active site is highly conserved and is not susceptible to mutations leading to drug resistance.
  • neuraminidase an ideal target for drug action, preventing the spread of the virus to surrounding cells by inhibiting neuraminidase.
  • neuraminidase inhibitors on the market are zanamivir and oseltamivir (trade name Tamiflu). Among them, Tamiflu is listed as a reserve medicine by governments of various countries for the treatment of influenza virus.
  • the flu virus attacks the respiratory system of the human body and is mainly distributed in the lung tissue.
  • Tamiflu has no antiviral effect.
  • it needs to be metabolized by the liver to become its active metabolite, oseltamivir carboxylate.
  • oseltamivir carboxylate does not form an effective enrichment in the lungs, and less than 10% of the drug is distributed to the lungs, so a higher dose is required to have an antiviral effect, but it also causes more side effects.
  • dizziness, diarrhea, nausea, vomiting and adverse reactions of the central nervous system Such as dizziness, diarrhea, nausea, vomiting and adverse reactions of the central nervous system.
  • a method for preparing oseltamivircarboxylic acid hydrochloride comprising the steps of:
  • the reaction route is as follows:
  • the step a is carried out in a mixed system of an organic solvent and an alkali solution, wherein the reaction temperature is 0 to 60 ° C.
  • the organic solvent in the step a is any one or more of N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, dichloromethane and tetrahydrofuran, and the base
  • the solution is any one of an aqueous solution of sodium hydrogencarbonate, an aqueous solution of sodium carbonate, an aqueous solution of potassium carbonate, and an aqueous solution of potassium acetate.
  • the step b is carried out in a mixed system of an organic solvent and a strong alkali solution, wherein the reaction temperature is 0 to 60 °C.
  • the organic solvent in the step b is any one or more of dimethyl sulfoxide, tetrahydrofuran, methanol, ethanol, propanol, isopropanol, butanol, dioxane and acetone
  • the strong alkali solution is any one of an aqueous potassium hydroxide solution, an aqueous sodium hydroxide solution, and an aqueous lithium hydroxide solution.
  • the step c is carried out in an organic solvent, which is any one of dichloromethane, ethyl acetate, acetonitrile, tetrahydrofuran, dioxane, acetone, diethyl ether, diisopropyl ether and chloroform or Any variety.
  • organic solvent which is any one of dichloromethane, ethyl acetate, acetonitrile, tetrahydrofuran, dioxane, acetone, diethyl ether, diisopropyl ether and chloroform or Any variety.
  • the step a comprises the following steps:
  • A1 mixing oseltamivir phosphate, sodium hydrogencarbonate, tetrahydrofuran and water until clarification to obtain a first system
  • the first solution is extracted with tert-butyl methyl ether to obtain an organic phase solution, and the organic phase solution is rotary evaporated to dryness to obtain the compound 2.
  • the step b comprises the following steps:
  • the step b1 is stirred at 0 to 60 ° C for at least one hour, and the step b3 is carried out under an ice bath condition of 0 to 4 ° C and the pH is adjusted to 2.
  • the step c comprises the following steps:
  • the step c1 is carried out under an ice bath condition of 0 to 4 ° C, and the step c2 is reacted for 0.5 to 3 hours after the ice bath is removed and heated to reflux, the second system of the step c3 The temperature is lowered to 20 to 25 ° C and reacted for at least 10 hours.
  • the reaction time in the step a2 is 10 to 12 hours
  • the stirring time in the step b1 is 1 to 2 hours
  • the reaction time in the step c3 is 10 to 12 hours.
  • a method for preparing an oseltamivir carboxylate hydrochloride atomization agent which comprises obtaining oseltamivir carboxylate by any of the aforementioned preparation methods of oseltamivir carboxylate hydrochloride After the acid salt, the following steps are also included:
  • the oseltamivir carboxylate hydrochloride atomizing agent contains 0 to 2% by mass of a surfactant.
  • the oseltamivir carboxylate hydrochloride nebulizer is processed into a lyophilized powder or a capsule or tablet.
  • the preparation method of the oseltamivir carboxylate hydrochloride provided by the invention can directly generate the active ingredient oseltamivir carboxylate after metabolism of Tamiflu in the human body, and can be prepared by the invention in practical application.
  • the oseltamivir carboxylate is administered directly to the human body.
  • the invention also directly forms oseltamivir carboxylate hydrochloride into an atomizing agent, and directly delivers the active ingredient to the respiratory tract and lung tissue through an atomizing device to exert an anti-influenza virus function, thereby not only avoiding the drug to the gastrointestinal tract Direct stimulation, while lower doses can be used to reduce possible adverse effects.
  • Figure 1 shows a nuclear magnetic resonance spectrum of oseltamivir hydrochloride salt 4 of one embodiment of the present invention.
  • the invention provides a method for preparing oseltamivircarboxylic acid hydrochloride, the specific reaction route of which is as follows:
  • step a is carried out, and in the organic solvent, oseltamivir phosphate and di-tert-butyldicarbonate (Boc) 2 O are reacted at 0 to 60 ° C under the action of a strong alkali solution to obtain a compound 2.
  • oseltamivir phosphate and di-tert-butyldicarbonate (Boc) 2 O are reacted at 0 to 60 ° C under the action of a strong alkali solution to obtain a compound 2.
  • the organic solvent and the alkali solution in this step together constitute the reaction system required for this step, and oseltamivir phosphate and di-tert-butyl dicarbonate are reacted in the reaction system.
  • the selection of the organic solvent in this step needs to consider the following factors: one is to dissolve the reactants and the product; the second is that it cannot participate in the reaction itself; the third is to facilitate separation from the reactants and products; the fourth is to be as low as possible or Non-toxic, correspondingly, the organic solvent may be selected from any one or more of N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, dichloromethane and tetrahydrofuran, and at the same time, elected After determining the type of organic solvent, the purity of the organic solvent should also be ensured to avoid introducing impurities into the system.
  • the alkali solution in the step a is any one of an aqueous solution of sodium hydrogencarbonate, an aqueous solution of sodium carbonate, an aqueous solution of potassium carbonate and an aqueous solution of potassium acetate, and those skilled in the art understand that the addition of the alkali solution makes the reaction system weakly alkaline.
  • a saturated aqueous solution of sodium hydrogencarbonate is used as a measure, that is, a pH of between 8 and 9, such a reaction system can ensure the stability of the resulting compound 2.
  • the reaction in the step a can be continued at 0 to 60 ° C, and the technical field The surgeon understands that the reaction temperature is related to the reaction rate, and the lower the reaction temperature, the lower the corresponding reaction rate.
  • the temperature can be controlled at a lower level in the initial stage, for example, 5 to 15 ° C, and after a reaction for a period of time, for example, 1 hour, the temperature is raised to 35 to 60 ° C, and then the reaction is continued until the reaction is completed.
  • the compound 2 is dissolved in the reaction system, and then a corresponding extraction step and a drying step are required to obtain the compound 2 in a solid form.
  • the designer understands that in order to realize the extraction step, the step is first required.
  • the water-soluble organic solvent in a is distilled off, and further, an aqueous phase containing the compound 2 is extracted by adding an extraction solvent, and then the organic phase in which the compound 2 is dissolved is subjected to dry-spinning to obtain a compound 2 in a solid form.
  • step b in the organic solvent, the compound 2 is hydrolyzed at 0 to 60 ° C under the action of a strong alkali solution to obtain a compound 3, wherein the organic solvent and the strong alkali solution in the step b are combined to form a step.
  • the reaction system of b Specifically, the action of the organic solvent in the step b is similar to that in the step a.
  • the selection principle can be referred to the selection principle in the step a.
  • the organic solvent in the step b can be selected from the group consisting of dimethyl sulfoxide, tetrahydrofuran, and methanol.
  • the strong alkali solution in the step b is used for hydrolyzing the ester group on the compound 2, and the strong alkali solution may be any one of an aqueous potassium hydroxide solution, an aqueous sodium hydroxide solution, and an aqueous lithium hydroxide solution.
  • the pH can be controlled between 13 and 14.
  • the designer understands that in order to realize the extraction washing step, the water-soluble organic solvent in the step b needs to be first distilled off, and then the extraction solvent is added, and thereafter different from the method in the step a, the extraction of the sodium salt containing the compound 3 is required in the step b.
  • the impurities in the aqueous phase are then precipitated to precipitate a solid of compound 3 after acidification of the aqueous phase.
  • step c is carried out, and in the organic solvent, the compound 3 is reacted with hydrogen chloride to obtain oseltamivir carboxylate hydrochloride 4.
  • the organic solvent in the step c is used alone as the reaction system, and accordingly, the organic solvent in the step c can be selected from dichloromethane, ethyl acetate, acetonitrile, tetrahydrofuran, dioxane, acetone, diethyl ether, and different. Any one or more of propyl ether and chloroform.
  • step a is to oseoseose phosphate
  • the amine group on the Wei has introduced a protecting group.
  • the tert-butoxycarbonyl group (Boc) is selected as the amine protecting group.
  • the p-methoxybenzyloxycarbonyl group, 2-(4-biphenyl) can also be selected. Any of isopropoxycarbonyl, 3,5-dimethoxyphenylisopropoxycarbonyl, trityl, 2-nitrophenylthio as an amine protecting group, these changes can eventually pass through hydrogen chloride The removal is carried out to achieve a synthetic scheme for completing the design of the present invention.
  • step a1 is performed, and oseltamivir phosphate, sodium hydrogencarbonate, tetrahydrofuran, and water are mixed and stirred until clarification to obtain a first system.
  • oseltamivir phosphate, sodium hydrogencarbonate, tetrahydrofuran, and water are mixed and stirred until clarification to obtain a first system.
  • there are various ways of feeding for example, sequentially adding oseltamivir phosphate, sodium hydrogencarbonate, tetrahydrofuran, and water to the reaction bottle, and putting all the materials into one at a time when placing each material; for example, sequentially to the reaction bottle
  • the oseltamivir phosphate, sodium hydrogencarbonate, tetrahydrofuran and water are added, and the method of placing each material is repeated in multiple batches; for example, oseltamivir phosphate, sodium hydrogencarbonate or tetrahydrofuran can be added with stirring. And water, but not in order
  • step a2 after adding a solution of di-tert-butyl dicarbonate in tetrahydrofuran to the first system under ice bath conditions of 0 to 4 ° C, the specific addition method is a dropping method, and all the drops are added. After the addition is completed, the reaction is carried out for at least 10 hours to obtain a first solution. Preferably, the reaction is carried out for 10 to 12 hours.
  • the first solution is extracted with tert-butyl methyl ether to obtain an organic phase solution, and the organic phase solution is rotary-dried to dryness to obtain the compound 2.
  • the tetrahydrofuran in the first solution is removed by a vacuum distillation method, and then an extraction step is performed by adding t-butyl methyl ether to the first solution, and then the organic phase is extracted, preferably, multiple extraction steps are performed and combined.
  • the organic phase was dried and then rotary evaporated to dryness to give the compound 2.
  • the compound 2 is an off-white solid.
  • step b1 is carried out, and the compound 2, methanol and an aqueous sodium hydroxide solution are mixed and stirred at 0 to 60 ° C for at least one hour to obtain a second solution.
  • the compound 2 is first charged into the reaction flask, and then methanol is added to be stirred, and then an aqueous sodium hydroxide solution is added while stirring.
  • the aqueous sodium hydroxide solution is a 4.5 N aqueous sodium hydroxide solution, to be described. After all the sodium hydroxide aqueous solution was added, stirring was continued for 1 hour to obtain the second solution.
  • step b2 is performed, and methanol in the second solution is removed by steam distillation under reduced pressure. Thereafter, water and tert-butyl methyl ether were added to wash to obtain an aqueous phase solution.
  • the action of the water in this step is similar to that of the tert-butyl methyl ether in the step a3, and accordingly, the water added in this step is used to extract the sodium salt of the product 3.
  • step b3 is carried out, and the pH of the aqueous phase solution is adjusted to 2 using hydrochloric acid under ice bath conditions of 0 to 4 ° C until the compound 3 is precipitated. Specifically, since the compound 3 is insoluble in the aqueous phase, accordingly, after adjusting the pH of the aqueous phase solution to be acidic, the sodium salt of the compound 3 is converted into the compound 3 and gradually precipitated from the aqueous phase.
  • step c1 hydrogen chloride gas is introduced into the ethyl acetate under ice bath conditions of 0 to 4 ° C to obtain a second system. Specifically, the hydrogen chloride gas is dried and then passed to ethyl acetate. It is understood by those skilled in the art that the hydrogen chloride gas is continuously introduced, and accordingly, continuous circulation can be achieved in conjunction with the gas circulation device and the drying device.
  • step c2 the compound 3 is added to the second system, and the ice bath is removed and heated to reflux for 0.5 to 3 hours. It is understood by those skilled in the art that the reaction after heating to reflux can ensure that the temperature of each reaction is the same, and that the temperature of the reaction can be made uniform with the temperature of the solvent, so that the reaction is reproducible, and is also constant and easy to control.
  • step c3 is performed to lower the temperature of the second system to 20 to 25 ° C and react for at least 10 hours until oseltamivircarboxylic acid hydrochloride 4 is precipitated. Specifically, after the precipitation of oseltamivircarboxylic acid hydrochloride 4, a filtration washing and drying step is carried out to obtain dried oseltamivircarboxylic acid hydrochloride salt 4.
  • the compound 2 1600 ml of methanol was added to the reactor, and 1600 ml of an aqueous solution containing 290 g of sodium hydroxide was added thereto with stirring, and the mixture was stirred at 25 ° C for 1 h.
  • the disappearance of the starting material by TLC was carried out, and methanol was removed by distillation under reduced pressure, and then 1 L of water was added.
  • the impurities were extracted with butyl methyl ether.
  • the pH was adjusted to pH 2 with concentrated hydrochloric acid in an ice-water bath. A large amount of white solid was precipitated and filtered to give 340 g of white solid compound 3.
  • the total yield of the two steps was 97.5%.
  • FIG. 1 shows a nuclear magnetic resonance spectrum of oseltamivir carboxylate hydrochloride 4 obtained by the present Preparation Example, and it can be seen from FIG. 1 that the obtained oseltamivir carboxylate hydrochloride 4 1 H NMR (400 MHz, D 2 O), ⁇ : 6.77 (s, 1H), 4.23 to 4.26 (m, 1H), 3.94 to 4.00 (m, 1H), 3.44 to 3.50 (m, 2H), 2.82 2.88 (m, 1H), 2.38 to 2.45 (m, 1H), 1.98 (s, 3H), 1.33 to 1.46 (m, 4H), 0.72 to 0.80 (m, 6H). It can be accurately judged from the nuclear magnetic resonance spectrum that the compound 4 is oseltamivircarboxylic acid hydrochloride.
  • oseltamivir carboxylate is a very effective inhibitor of influenza virus neuraminidase, and the specific principle is that since the neuraminidase molecular structure is composed of four identical parts, the shape Just like a "field" word, the center is a hole, which is where sialic acid combines and hydrolyzes sialic acid, and oseltamivir carboxylate can be inserted into this cavity and can be combined with neuraminic acid. The enzyme binds so strongly that the sialic acid on the cells is blocked and the neuraminidase activity is inhibited.
  • oseltamivir carboxylate When oseltamivir carboxylate enters the human body, it competitively binds to the active site of the influenza virus neuraminidase and releases it from the infected host cell by interfering with the virus, thereby reducing the influenza A or B virus. propagation. Specifically, oseltamivir carboxylate can reach all target tissues invaded by influenza virus, accumulate in lung, tracheal, bronchoalveolar lavage fluid, nasal mucosa, middle ear, etc., but it is associated with human plasma protein. The combination can be ignored (not more than 3%).
  • the peak plasma concentration of oseltamivir carboxylate is 6 to 10 hours, excreted by the kidneys, and the renal clearance (18.8 L/h) exceeds the glomerular filtration rate (7.5 L). /h), indicating that in addition to glomerular filtration, there is a pathway for renal tubular excretion.
  • the existing influenza patients achieve therapeutic purposes by oral administration of Tamiflu, but more than 90% of the absorption loss is obtained before oral administration of Tamiflu to the lungs of the affected site, and Duffy is directly prepared by the preparation method provided by the present invention.
  • the active metabolite oseltamivircarboxylic acid hydrochloride which can make oseltamivir carboxylate hydrochloride into the inhalation preparation directly acts on the lungs, has a faster onset of action and less loss, so it is expected to use The effective dose will be reduced, thereby reducing the toxicity effect.
  • a mixture of oseltamivir carboxylate hydrochloride and an osmotic pressure adjusting agent is prepared, wherein the oseltamivir carboxylate hydrochloride is contained in an amount of 5 to 200 mg.
  • the mixed liquid prepared in this step is an isotonic solution.
  • the amount of the osmotic pressure adjusting agent can be increased or decreased according to the actual situation, as long as the oseltamivir carboxylate dissolved in the osmotic pressure adjusting agent is ensured.
  • the content of the acid salt may be 5 to 200 mg.
  • the osmotic pressure adjusting agent may be selected from one or more of sodium chloride, glucose, sorbitol, glycerin, PEG, propylene glycol, mannitol, and lactose. Thereafter, a pH buffer was added to the mixture to adjust the pH to 3.5 to 8.5 to obtain an oseltamivir carboxylate hydrochloride atomizing agent.
  • the pH buffer may be any one of phosphoric acid, citric acid, carbonic acid, acetic acid, barbituric acid, borate, citrate, and phosphate (such as disodium hydrogen phosphate or sodium dihydrogen phosphate).
  • the oseltamivir carboxylate aerosol nebulizer contains 0 to 2% by mass of surfactant.
  • the surfactant is a physiologically acceptable suitable surfactant, and the following materials are generally selected as surfactants: sorbitan trioleate, sorbitan monooleate, sorbitan monolaurate, polyoxygen Ethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitan monooleate, natural lecithin, oleoyl polyoxyethylene (2) ether, stearyl polyoxyethylene (2) Ether, lauroyl polyoxyethylene (2) ether, lauroyl polyoxyethylene (4) ether, ethylene oxide and propylene oxide block copolymer, synthetic lecithin, diethylene glycol dioleate, tetrahydroanthracene oleate Ester, ethyl oleate, glycerol monooleate, polyethylene glycol 400, and glycerol
  • Formulation 1 oseltamivir carboxylate 10mg, disodium hydrogen phosphate 14.20mg, sodium chloride 18.04mg, polyoxyethylene (20) sorbitan monooleate 4mg, the above substances are taken according to the formula Then add water for injection to 2ml, mix well, transfer to cleaned glass ampoules, melt seal, steam high pressure 120 ° C sterilization for 12 minutes.
  • Formulation 2 oseltamivir carboxylate 40mg, disodium hydrogen phosphate 14.20mg, chlorination Sodium 18.04mg, polyoxyethylene (20) sorbitan monooleate 4mg, the above substances are added according to the formula and then added to the injection water to 2ml, mixed evenly, transferred to the cleaned glass ampoules, melt sealed, The steam is sterilized for 12 minutes at 120 degrees Celsius.
  • Formulation 3 oseltamivir carboxylate 60mg, sodium chloride 18.04mg, the above substances are added according to the formula and then added to the injection water to 2ml, mixed evenly, 0.22um filter membrane filter sterilization, transferred to cleaned The glass ampoule is sealed and sealed.
  • the oseltamivir carboxylate hydrochloride nebulizer is processed into a lyophilized powder, for example a specific formulation: oseltamivir carboxylate 30 mg, glucose 200 mg, sodium chloride 3.6mg, the above substances are added according to the formula and then added to the injection water to 4ml, dissolved and stirred evenly, filtered and sterilized, quantitative liquid filling, half-pressure plug, placed in a freeze dryer, freeze-dried, to be freeze-dried , full pressure plug. Before clinical use, add 4.0 ml of water for injection and shake for 5 to 10 seconds until dissolved.
  • the oseltamivir carboxylate hydrochloride nebulizer is processed into capsules or tablets, for example a specific formulation: oseltamivir carboxylate 5 to 60 mg, mannitol 80 ⁇ 100mg, lactose 20 ⁇ 40mg, sodium chloride 3.6mg, the above substances in accordance with the formula, three-dimensional mixer or V-type mixer mixed evenly, quantitatively divided into capsules or using a tablet press to suppress the dosage size of 100 ⁇ 200mg small pieces.
  • a piece of water plus 4.0 ml of water for injection or take a capsule and pour out the contents and add 4.0 ml of water for injection, shake for 5 to 10 seconds until dissolved.
  • the human respiratory system is a relatively fragile physiological system, especially under the influence of factors such as air pollution and smoking, and the respiratory diseases generally show an upward trend.
  • inhaled drugs are preferred for the treatment of respiratory diseases.
  • some inhaled drugs such as aerosols or powders are not easy to use due to poor adaptability, and the clinical treatment effect is not good.
  • the atomized inhalation aqueous solution is atomized by a special atomizer, and the diameter of the formed drug droplet is generally between 0.5 and 12 um, which is favorable for the drug to be directly inhaled into the respiratory tract, the local concentration is relatively high, and the dose is relatively small.
  • the formula 1 , the formula 2 and the formula 3 are used to illustrate the breathing simulator (USP 35-1601) Chapter) and the NGI impactor (Chinese Pharmacopoeia 2015 Edition - Device 3) are in vitro evaluation methods to simulate the percentage of drugs that can be inhaled by the human body after atomization. The results are as follows:

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Abstract

一种奥司他韦羧酸盐酸盐的制备方法，包括如下步骤： a. 在磷酸奥司他韦1上的胺基引入保护基A得到化合物2； b. 在强碱作用下将化合物2上的酯基水解后得到化合物3； c. 通过氯化氢脱去化合物3的保护基A得到奥司他韦羧酸盐酸盐4；反应路线如公式(I) 直接合成的奥司他韦羧酸盐酸盐及其雾化剂可以避免药物对胃肠道的直接刺激作用，通过可以使用更低的剂量从而降低可能的不良反应。

Description

奥司他韦羧酸盐酸盐及其雾化剂的制备方法 技术领域
本发明属于药物合成和制剂领域，具体涉及一种抗流感药物的制备，特别是指奥司他韦羧酸盐酸盐及其雾化剂的制备方法。
背景技术
流感病毒是一种造成人类及动物患流行性感冒的病毒，在分类学上，流感病毒属于正黏液病毒科，它会造成急性上呼吸道感染，并借由空气迅速的传播，在世界各地常会有周期性的大流行。根据流感病毒核蛋白的抗原性可以分为甲、乙和丙三类。其中甲型和乙型容易造成流感的大流行，而丙型以散在形式出现，一般不引起流行。
流感病毒是一种呈球状(直径80-120nm)并含有节段基因组的负链RNA病毒。甲型和乙型流感病毒含有8个RNA节段，每个RNA片段是由病毒核蛋白包裹并由聚合酶复合物相关联。核蛋白、RNA和聚合酶形成的复合物颗粒，被称之为核糖核蛋白颗粒，被含有基质蛋白M1和膜蛋白M2组成的脂质膜所包裹。两种刺突蛋白质嵌入到脂质膜中并伸向病毒表面：分别为棒状的血凝素和蘑菇状的神经氨酸酶。这两类蛋白对于病毒的复制起着重要作用。
流感是一种传染性很强的疾病，主要由人体呼吸道分泌物传播，一般来说流感感染是通过咳嗽或者打喷嚏产生的飞沫传播。感染通常认为是从气管支气管上皮组织开始，然后蔓延。组织学研究表明流感病毒复制发生在整个上呼吸道和下呼吸道。流感疾病的发作与病毒复制的进展息息相关。
虽然流感病毒在呼吸道发生复制，但是会影响到全身的状态。流感病毒的感染和复制会引起宿主细胞的死亡，而这会导致呼吸道发炎，并引发快速的免疫反应，从而导致全身出现症状，包括全身乏力、发烧、寒颤、头痛、食欲不振、肌肉酸痛和头晕。这些早期的全身症状通常伴随有呼吸道症状，如干咳、流鼻涕、打喷嚏、咽痛。低频的 症状包括有排痰性咳嗽、声音嘶哑、胸骨后疼痛。全身症状通常持续3-4天，然而咳嗽和身体不适可能在退烧后持续2周。感染流感后，还易诱发严重并发症，如并发肺炎、心肌炎、脑膜炎等严重疾病，甚至引起死亡。
大约每10-40年，由于新的流感病毒抗原的出现，会出现全球性的流感大流行。而由于人们很少或者根本没有抵抗新型病毒的免疫力，流感大流行可以影响到世界人口的50％。关于全球流感大流行已有数百年的报道。有据可查的流感大流行分别发生在1918年(西班牙流感)、1957年(亚洲流感)和1968年(香港流感)，造成3000万、100万和80万人死亡。而在2009年爆发的H1N1猪流感波及全球200多个国家和地区，有20000人死亡。
在控制流感方面主要有两个方法：1)预防，接种疫苗或者其他抗病毒的预防性药物；2)使用抗病毒药物治疗。使用后一种办法的目的是缓解病毒感染后的症状以及缩短感染持续时间，同时预防其他并发症如支气管炎和肺炎。
高危人群一般建议接种疫苗以预防感染，如老人、儿童、严重慢性病患者、免疫力低下及可能密切接触患者的人员。由于流感病毒的高变异性增大了人们应对流行性感冒的难度，人们无法准确预测即将流行的病毒亚型，便不能有针对性地进行预防性疫苗接种。另一方面，每隔数十年便会发生的抗原转变更会产生根本就没有疫苗的流感新毒株。
M2抑制剂金刚烷胺和金刚乙胺这两个药物是在20世纪60年代发现的，在80年代开始上市销售用于治疗流感。这两个药物均是含10个碳的三元环取代的一级胺。M2离子通道在病毒进入宿主细胞后进行脱壳复制时起到了重要作用。这两个药物通过抑制M2离子通道发挥抗病毒作用。由于M2蛋白仅在甲型流感中有表达，因此M2抑制剂对乙型流感没有治疗作用。这两个药物会造成比较显著的肠胃道不良反应。同时金刚烷胺对中枢神经系统也会产生不良影响。最新的研究发现，在临床上流感病毒株已经对该类药物产生耐药性，限制了该类药 物在流感治疗中的使用。
神经氨酸酶是糖苷水解酶，在甲型和乙型流感病毒均有表达。当成熟的流感病毒经出芽的方式脱离宿主细胞之后，病毒表面的血凝素会经由唾液酸受体与宿主细胞膜保持联系，需要由神经氨酸酶将唾液酸水解，切断病毒与宿主细胞的最后联系，使病毒能顺利从宿主细胞中释放，继而感染下一个宿主细胞。同时神经氨酸酶活性位点的胺基酸序列是高度保守的，不易产生突变从而导致耐药。这使得神经氨酸酶成为一个理想的药物作用靶点，通过抑制神经氨酸酶可以阻止病毒向周围细胞的扩散。目前市面上常用的神经氨酸酶抑制剂有扎那米韦和奥司他韦(商品名达菲)。其中达菲被各国政府列为储备药品用于流感病毒的治疗。
流感病毒攻击人体的呼吸系统，主要分布在肺组织中。达菲作为前体药，本身没有抗病毒疗效，口服后需要经过肝脏代谢水解成为其活性代谢产物-奥司他韦羧酸盐才能起作用。但奥司他韦羧酸盐不能在肺部形成有效的富集，只有小于10％的药物分布到肺部，因此需要较高的剂量才能起到抗病毒效果，但也会造成较多的副作用，如眩晕、腹泻、恶心、呕吐以及中枢神经系统的不良反应等。
发明内容
针对现有技术存在的技术缺陷，根据本发明的一个方面，提供一种奥司他韦羧酸盐酸盐的制备方法，包括如下步骤：
a.在磷酸奥司他韦1上的胺基引入保护基A得到化合物2，所述保护基A为叔丁氧羰基，对甲氧基苄氧羰基，2-(4-联苯)异丙氧羰基，3，5-二甲氧基苯基异丙氧羰基，三苯甲基，2-硝基苯硫基中的任一种；
b.在强碱作用下将所述化合物2上的酯基水解后得到化合物3；
c.通过氯化氢脱去所述化合物3的保护基A得到奥司他韦羧酸盐酸盐4；
反应路线如下：
Figure PCTCN2017000426-appb-000001
优选地，所述步骤a在有机溶剂和碱溶液的混合体系中完成，其中，反应温度为0～60℃.
优选地，所述步骤a中有机溶剂为N，N-二甲基甲酰胺、二甲亚砜、N-甲基吡咯烷酮、二氯甲烷和四氢呋喃中的任一种或任几种，所述碱溶液为碳酸氢钠水溶液、碳酸钠水溶液、碳酸钾水溶液和乙酸钾水溶液中的任一种。
优选地，所述步骤b在有机溶剂和强碱溶液的混合体系中完成，其中，反应温度为0～60℃。
优选地，所述步骤b中有机溶剂为二甲亚砜、四氢呋喃、甲醇、乙醇、丙醇、异丙醇、丁醇、二氧六环和丙酮中的任一种或任多种，所述强碱溶液为氢氧化钾水溶液、氢氧化钠水溶液和氢氧化锂水溶液中的任一种。
优选地，所述步骤c在有机溶剂中完成，所述有机溶剂为二氯甲烷、乙酸乙酯、乙腈、四氢呋喃、二氧六环、丙酮、乙醚、异丙醚和氯仿中的任一种或任多种。
优选地，所述步骤a包括如下步骤：
a1.将磷酸奥司他韦、碳酸氢钠、四氢呋喃以及水混合搅拌至澄清得到第一体系；
a2.在0～4℃的冰浴条件下，向所述第一体系中加入二叔丁基二碳酸酯的四氢呋喃溶液后反应至少10小时得到第一溶液；
a3.蒸干所述第一溶液中的有机相后，使用叔丁基甲基醚对所述第一溶液萃取得到有机相溶液，将所述有机相溶液旋蒸至干得到所述化合物2。
优选地，所述步骤b包括如下步骤：
b1.将所述化合物2、甲醇和氢氧化钠水溶液混合搅拌得到第二溶液；
b2.通过减压旋蒸去除所述第二溶液中的甲醇，之后加入水和叔丁基甲基醚洗涤得到水相溶液；
b3.使用盐酸将所述水相溶液的pH值调至酸性直至析出化合物3。
优选地，所述步骤b1在0～60℃搅拌至少一小时，所述步骤b3在0～4℃的冰浴条件下进行并将pH值调整至2。
优选地，所述步骤c包括如下步骤：
c1.向乙酸乙酯中通入氯化氢气体得到第二体系；
c2.向所述第二体系中加入所述化合物3加热至回流；
c3.将所述第二体系降温后反应直至析出奥司他韦羧酸盐酸盐4。
优选地，所述步骤c1在0～4℃的冰浴条件下进行，所述步骤c2在撤去冰浴并加热至回流后反应0.5～3小时，所述步骤c3中的所述第二体系的温度降到20～25℃并反应至少10小时。
优选地，所述步骤a2中的反应时间为10～12小时，所述步骤b1中的搅拌时间为1～2小时，所述步骤c3中的反应时间为10～12小时。
根据本发明的另一方面，还提供一种奥司他韦羧酸盐酸盐雾化剂的制备方法，通过前述任一种奥司他韦羧酸盐酸盐制备方法获得奥司他韦羧酸盐酸盐后，还包括如下步骤：
i.制备奥司他韦羧酸盐酸盐与渗透压调节剂的混合液，其中，所述奥司他韦羧酸盐酸盐的含量为5～200mg；
ii.加入pH缓冲剂将所述步骤i中的混合液的pH值调节至3.5～8.5得到奥司他韦羧酸盐酸盐雾化剂。
优选地，所述奥司他韦羧酸盐酸盐雾化剂中含有0～2％质量百分比的表面活性剂。
优选地，所述奥司他韦羧酸盐酸盐雾化剂被加工为冻干粉或者胶囊或者片剂。
本发明提供的奥司他韦羧酸盐酸盐的制备方法，能够直接生成达菲在人体内代谢后的活性成分奥司他韦羧酸盐，在实际的应用中，可以将通过本发明制备的奥司他韦羧酸盐酸盐直接向人体给药。同时，本发明还将奥司他韦羧酸盐酸盐直接制成雾化剂，通过雾化装置直接将活性成分输送到呼吸道及肺组织发挥抗流感病毒作用，不仅可以避免药物对胃肠道的直接刺激作用，同时可以使用更低的剂量从而降低可能的不良反应。
附图说明
图1示出了本发明的一个实施例的，奥司他韦羧酸盐酸盐4的核磁共振氢谱。
具体实施方式
本发明提供制备奥司他韦羧酸盐酸盐的方法，其具体的反应路线如下：
Figure PCTCN2017000426-appb-000002
结合上述反应路线，奥司他韦羧酸盐酸盐的制备方法具体如下：
首先执行步骤a，在有机溶剂中，磷酸奥司他韦与二叔丁基二碳酸酯(Boc)2O在强碱溶液的作用下在0～60℃反应得到化合物2。本领域技术人员理解，本步骤中的有机溶剂和碱溶液共同组成本步骤所需的反应体系，磷酸奥司他韦与二叔丁基二碳酸酯在此反应体系中进行反应。具体地，本步骤中有机溶剂的选择需要考虑以下因素：一是能溶解反应物和产物；二是本身不能参加反应；三是要便于与反应物和产物的分离；四是尽可能低毒或无毒，相应地，有机溶剂可以选择N，N-二甲基甲酰胺、二甲亚砜、N-甲基吡咯烷酮、二氯甲烷和四氢呋喃中的任一种或任多种，同时，当选定有机溶剂种类后，还应当保证有机溶剂的纯度，避免向体系中引入杂质。
进一步地，步骤a中的碱溶液为碳酸氢钠水溶液、碳酸钠水溶液、碳酸钾水溶液和乙酸钾水溶液中的任一种，本领域技术人员理解，碱溶液的加入使反应体系呈现弱碱性，优选地，以饱和的碳酸氢钠水溶液作为衡量标准，即pH值在8-9之间，这样的反应体系可以保证生成的化合物2的稳定性。
进一步地，步骤a中的反应在0～60℃均可以持续进行，本领域技 术人员理解，反应温度与反应速度相关联，反应温度越低，则相应的反应速度也越低。优选地，在初始阶段温度可以控制在较低水平，例如5～15℃，反应一段时间后，例如反应1小时，开始升温到35～60℃，之后再持续反应直至反应结束。
进一步地，步骤a反应完成后，化合物2溶解于反应体系中，之后还需要相应的萃取步骤以及干燥步骤以获得固体形态的化合物2，本领域设计人员理解，要实现萃取步骤，需要首先将步骤a中的水溶性有机溶剂蒸除，进而加入萃取溶剂萃取含有化合物2的水相，之后对溶解有化合物2的有机相进行干燥旋蒸得到固体形态的化合物2。
进一步地，执行步骤b，在有机溶剂中，所述化合物2在强碱溶液的作用下在0～60℃发生水解反应得到化合物3，其中，步骤b中的有机溶剂和强碱溶液共同组成步骤b的反应体系。具体地，步骤b中的有机溶剂的作用与步骤a中是类似的，其选用原则可参照步骤a中的选用原则，例如，步骤b中的有机溶剂可以选择二甲亚砜、四氢呋喃、甲醇、乙醇、丙醇、异丙醇、丁醇、二氧六环和丙酮中的任一种或任多种。更为具体地，步骤b中的强碱溶液用于对化合物2上的酯基水解，所述强碱溶液可以选用氢氧化钾水溶液、氢氧化钠水溶液和氢氧化锂水溶液中的任一种，其pH值可以控制在13～14，反应完成后，还需要相应的萃取洗涤步骤以及酸化沉淀步骤以获得固体形态的化合物3。本领域设计人员理解，要实现萃取洗涤步骤，需要首先将步骤b中的水溶性有机溶剂蒸除，进而加入萃取溶剂，此后不同于步骤a中的方式，步骤b中需要萃取含有化合物3钠盐的水相中的杂质，之后对水相酸化后沉淀析出化合物3固体。
进一步地，执行步骤c，在有机溶剂中，所述化合物3与氯化氢反应得到奥司他韦羧酸盐酸盐4。本领域技术人员理解，步骤c中的有机溶剂单独作为反应体系，相应地，步骤c中的有机溶剂可以选择二氯甲烷、乙酸乙酯、乙腈、四氢呋喃、二氧六环、丙酮、乙醚、异丙醚和氯仿中的任一种或任多种。
进一步地，本领域技术人员理解，步骤a的目的在于在磷酸奥司他 韦上的胺基引入保护基，上述实施例中选择叔丁氧羰基(Boc)作为胺基保护基，作为一些变化，还可以选择对甲氧基苄氧羰基，2-(4-联苯)异丙氧羰基，3，5-二甲氧基苯基异丙氧羰基，三苯甲基，2-硝基苯硫基中的任一种作为胺基保护基，这些变化最终都可以通过氯化氢脱去，进而实现完成本发明设计的合成方案。
作为本发明的一个具体的实施例，包括如下步骤：
首先执行步骤a1，将磷酸奥司他韦、碳酸氢钠、四氢呋喃以及水混合搅拌至澄清得到第一体系。具体地，投料的方式有多种，例如，依次向反应瓶中投入磷酸奥司他韦、碳酸氢钠、四氢呋喃以及水，且投放每种材料时一次性全部投入；又例如，依次向反应瓶中投入磷酸奥司他韦、碳酸氢钠、四氢呋喃以及水，且投放每种材料的方法为分批多次循环投入；又例如，可以边搅拌边投入磷酸奥司他韦、碳酸氢钠、四氢呋喃以及水，但并不按照顺序投入。
进一步地，执行步骤a2，在0～4℃的冰浴条件下，向所述第一体系中加入二叔丁基二碳酸酯的四氢呋喃溶液后，具体的加入方式为滴加的方式，全部滴加完毕后反应至少10小时得到第一溶液。优选地，反应10～12小时。
进一步地，执行步骤a3，蒸干有机相后，使用叔丁基甲基醚对所述第一溶液萃取得到有机相溶液，将所述有机相溶液旋蒸至干得到所述化合物2。具体地，首先通过减压旋蒸法除去所述第一溶液中的四氢呋喃，之后向第一溶液中加入叔丁基甲基醚执行萃取步骤，再提取有机相，优选地，执行多次萃取步骤并合并有机相经干燥后再旋蒸至完全干燥，得到所述化合物2。所述化合物2为类白色固体。
进一步地，执行步骤b1，将所述化合物2、甲醇和氢氧化钠水溶液混合并在0～60℃搅拌至少一小时得到第二溶液。具体地，先向反应瓶中投入所述化合物2，之后再加入甲醇搅拌，之后边搅拌边加入氢氧化钠水溶液，优选地，所述氢氧化钠水溶液为4.5N氢氧化钠水溶液，待所述氢氧化钠水溶液全部加入后，再持续搅拌1小时得到所述第二溶液。
进一步地，执行步骤b2，通过减压旋蒸去除所述第二溶液中的甲醇， 之后加入水和叔丁基甲基醚洗涤得到水相溶液。具体地，本步骤的水与步骤a3中的叔丁基甲基醚的作用是类似的，相应地，本步骤中加入的水用于萃取产物3的钠盐。
进一步地，执行步骤b3，在0～4℃的冰浴条件下，使用盐酸将所述水相溶液的pH值调至2直至析出化合物3。具体地，由于所述化合物3不溶于水相，相应地，调节所述水相溶液的pH值为酸性后，化合物3的钠盐转化为化合物3并逐渐从水相沉淀析出。
进一步地，执行步骤c1，在0～4℃的冰浴条件下，向乙酸乙酯中通入氯化氢气体得到第二体系。具体地，所述氯化氢气体经过干燥后再通入乙酸乙酯中。本领域技术人员理解，所述氯化氢气体是持续通入的，相应地，可以配合气体循环装置以及干燥装置实现循环持续通入。
进一步地，执行步骤c2，向所述第二体系中加入所述化合物3，撤去冰浴并加热至回流后反应0.5～3小时。本领域技术人员理解，加热至回流后反应，可以保证每次反应的温度相同，并且可以使反应的温度与溶剂温度一致，使得反应有重复性，而且还恒定易于控制。
进一步地，执行步骤c3，将所述第二体系温度降到20～25℃并反应至少10小时直至析出奥司他韦羧酸盐酸盐4。具体地，析出奥司他韦羧酸盐酸盐4后还进行过滤洗涤烘干步骤，得到干燥的奥司他韦羧酸盐酸盐4。
更为具体地，以下示出了奥司他韦羧酸盐酸盐的制备实施例：
首先，向反应器中投入372g磷酸奥司他韦，381g碳酸氢钠，3600ml四氢呋喃，900ml水，搅拌溶清，0～4℃冰浴下滴加238g二叔丁基二碳酸酯的四氢呋喃溶液，滴毕，25℃下反应过夜，减压旋蒸除去四氢呋喃，叔丁基甲基醚萃取(2L*2)，合并有机相减压旋蒸至干，得到化合物2。
之后，向反应器中加入化合物2，1600ml甲醇，搅拌下加入含290g氢氧化钠的1600ml水溶液，25℃搅拌1h，通过TLC检测原料消失，减压旋蒸除去甲醇，再加入1L水，1L叔丁基甲基醚萃取杂质，水相冰浴下用浓盐酸调节pH＝2，析出大量白色固体，过滤烘干得340g白色固体化合物3，两步总产率为97.5％。
之后，0～4℃冰浴下向乙酸乙酯中通入干燥的氯化氢气体，后在搅拌下加入前面得到的化合物3，撤去冰浴，升温至回流后反应1h，降温至25℃反应过夜，析出大量白色固体，抽滤，烘干得280g白色固体即奥司他韦羧酸盐酸盐4，产率为98.6％。
具体地，图1示出了通过本制备实施例得到的奥司他韦羧酸盐酸盐4的核磁共振氢谱，从图1可以看出，得到的奥司他韦羧酸盐酸盐4的1H NMR(400MHz，D2O)，δ：6.77(s，1H)，4.23～4.26(m，1H)，3.94～4.00(m，1H)，3.44～3.50(m，2H)，2.82～2.88(m，1H)，2.38～2.45(m，1H)，1.98(s，3H)，1.33～1.46(m，4H)，0.72～0.80(m，6H)。从核磁共振图谱可以准确判断出化合物4即为奥司他韦羧酸盐酸盐。
本领域技术人员理解，奥司他韦羧酸盐是非常有效的流感病毒神经氨酸酶的抑制剂，其具体原理为：由于神经氨酸酶分子结构是由4个一模一样的部分组成的，形状就像一个“田”字，正中央是个空穴，那就是和唾液酸结合并将唾液酸水解的地方，而奥司他韦羧酸盐可以塞进这个空穴里面，并且可以与神经氨酸酶结合得很牢固，这样细胞上的唾液酸就被堵在外面，神经氨酸酶的活性就可以被抑制住了。当奥司他韦羧酸盐进入人体后，竞争性地与流感病毒神经氨酸酶的活动位点结合，通过干扰病毒从被感染的宿主细胞中释放，从而减少甲型或乙型流感病毒的传播。具体地，奥司他韦羧酸盐可以到达所有被流感病毒侵犯的靶组织，在肺、气管、支气管肺泡灌洗液及鼻黏膜、中耳等部位都有积聚，但其与人血浆蛋白的结合可以忽略不计(不超过3％)。对于大多数受试者，奥司他韦羧酸盐的达峰血浆浓度半衰期为6～10小时，由肾脏排泄，肾脏的清除率(18.8L/h)超过肾小球滤过率(7.5L/h)，表明除肾小球滤过外还有肾小管排泄这一途径。
进一步地，现有的流感患者通过口服达菲达到治疗目的，但口服达菲到达作用部位肺部前，会有90％以上的吸收损失，而通过本发明提供的制备方法直接制成达菲的活性代谢产物奥司他韦羧酸盐酸盐，进而可以将奥司他韦羧酸盐酸盐制成吸入制剂直接作用于肺部，起效速度快于口服，而且损失较少，这样预期使用的有效剂量会降低，从而降低毒副 作用。
作为本发明的另一具体实施方式，还提供一种奥司他韦羧酸盐酸盐雾化剂的制备方法，包括如下步骤：
首先制备奥司他韦羧酸盐酸盐与渗透压调节剂的混合液，其中，所述奥司他韦羧酸盐酸盐的含量为5～200mg。本领域技术人员理解，本步骤制成的混合液为等渗溶液，具体地，渗透压调节剂的添加量可以根据实际情况增减，只要保证溶解在渗透压调节剂中的奥司他韦羧酸盐酸盐的含量在5～200mg即可。更为具体地，奥司他韦羧酸盐酸盐的含量越高，则相应的减少渗透压调节剂的添加量。优选地，渗透压调节剂可以选择氯化钠、葡萄糖、山梨醇、甘油、PEG、丙二醇、甘露醇、乳糖中的一种或者多种。之后在所述混合液中加入pH缓冲剂将pH值调节至3.5～8.5得到奥司他韦羧酸盐酸盐雾化剂。具体地，pH缓冲剂可以选用磷酸、柠檬酸、碳酸、乙酸、巴比妥酸、硼酸盐、柠檬酸盐和磷酸盐(如磷酸氢二钠、磷酸二氢钠)中的任一种。
在一个优选地的实施例中，所述奥司他韦羧酸盐酸盐雾化剂中含有0～2％质量百分比的表面活性剂。所述表面活性剂是生理可接受的适宜表面活性剂，通常选用以下物质作为表面活性剂：脱水山梨醇三油酸酯、脱水山梨醇单油酸酯、脱水山梨醇单月桂酸酯、聚氧乙烯(20)脱水山梨醇单月桂酸酯、聚氧乙烯(20)脱水山梨醇单油酸酯、天然卵磷酯、油酰聚氧乙烯(2)醚、硬脂酰聚氧乙烯(2)醚、月桂酰聚氧乙烯(2)醚、月桂酰聚氧乙烯(4)醚、氧化乙烯和氧化丙烯嵌段共聚物、合成卵磷酯、二甘醇二油酸酯、油酸四氢糠酯、油酸乙酯、甘油单油酸酯、聚乙二醇400和甘油单月桂酸酯等。
为了更好的说明雾化剂的制备方法，以下示出了三个具体的配方：
配方一：奥司他韦羧酸盐酸盐10mg，磷酸氢二钠14.20mg，氯化钠18.04mg，聚氧乙烯(20)脱水山梨醇单油酸酯4mg，将上述各物质按照配方量取再加入注射用水到2ml，混合均匀、转移至已清洁的玻璃安剖瓶，熔封，蒸汽高压120摄氏度灭菌12分钟。
配方二：奥司他韦羧酸盐酸盐40mg，磷酸氢二钠14.20mg，氯化 钠18.04mg，聚氧乙烯(20)脱水山梨醇单油酸酯4mg，将上述各物质按照配方量取再加入注射用水到2ml，混合均匀、转移至已清洁的玻璃安剖瓶，熔封，蒸汽高压120摄氏度灭菌12分钟。
配方三：奥司他韦羧酸盐酸盐60mg，氯化钠18.04mg，将上述各物质按照配方量取再加入注射用水到2ml，混合均匀、0.22um滤膜过滤除菌，转移至已清洁的玻璃安剖瓶，熔封。
在一个变化例中，所述奥司他韦羧酸盐酸盐雾化剂被加工为冻干粉，例如一个具体配方为：奥司他韦羧酸盐酸盐30mg，葡萄糖200mg，氯化钠3.6mg，将上述各物质按照配方量取再加入注射用水到4ml，溶解并搅拌均匀、过滤除菌、定量分液灌装，半压塞，放入冷冻干燥机中冷冻干燥，待冷冻干燥完成，全压塞。临床使用前，加注射用水4.0ml，振摇5～10秒至溶解备用。
在一个变化例中，所述奥司他韦羧酸盐酸盐雾化剂被加工为胶囊或者片剂，例如一个具体配方为：奥司他韦羧酸盐酸盐5～60mg，甘露醇80～100mg，乳糖20～40mg，氯化钠3.6mg，将上述各物质按照配方量取、三维混合器或V型混合器混合均匀、定量分装至胶囊或使用压片机压制剂量规格为100～200mg的小片。临床使用前，取一片加注射用水4.0ml，或取一胶囊将内容物倒出并加注射用水4.0ml，振摇5～10秒至溶解备用。
本领域技术人员理解，人类的呼吸系统是一个相对脆弱的生理系统，特别是在大气污染、吸烟等因素影响下，呼吸系统的疾病总体呈上升趋势。从临床角度来看，治疗呼吸系统疾病首选吸入类药物。但老人、小孩或部分病患在使用吸入类药物时，部分吸入类药物如气雾剂或粉雾剂，因适应性差，导致不易使用，临床治疗效果不佳。而雾化吸入水溶液通过专用雾化器的雾化，形成的药物雾滴直径一般在0.5～12um之间，有利于药物被直接吸入至呼吸道，局部浓度相对较高，给药剂量相对较少，且相比气雾剂或粉雾剂而言，患者的耐受性大大提高。本发明中，以配方一、配方二和配方三为说明，以呼吸模拟器(美国药典USP35-1601 章节)和NGI撞击器(中国药典2015版-装置3)为体外评价手段，模拟评价药物雾化后可被人体吸入的百分率，结果如下表：
试样 递送剂量％ 体外沉积率(FPF) 微细粒子剂量
配方一 35.5％ 48.5％ 31％
配方二 31.1％ 52.8％ 28％
配方三 25.7％ 57.0％ 27％
以上对本发明的具体实施例进行了描述。需要理解的是，本发明并不局限于上述特定实施方式，本领域技术人员可以在权利要求的范围内做出各种变形或修改，这并不影响本发明的实质内容。

Claims (15)

  1. 奥司他韦羧酸盐酸盐的制备方法，其特征在于，包括如下步骤：
    a.在磷酸奥司他韦1上的胺基引入保护基A得到化合物2，所述保护基A为叔丁氧羰基，对甲氧基苄氧羰基，2-(4-联苯)异丙氧羰基，3，5-二甲氧基苯基异丙氧羰基，三苯甲基，2-硝基苯硫基中的任一种；
    b.在强碱作用下将所述化合物2上的酯基水解后得到化合物3；
    c.通过氯化氢脱去所述化合物3的保护基A得到奥司他韦羧酸盐酸盐4；
    反应路线如下：
    Figure PCTCN2017000426-appb-100001
  2. 根据权利要求1所述的制备方法，其特征在于，所述步骤a在有机溶剂和碱溶液的混合体系中完成，其中，反应温度为0～60℃。
  3. 根据权利要求2所述的制备方法，其特征在于，所述有机溶剂为N，N-二甲基甲酰胺、二甲亚砜、N-甲基吡咯烷酮、二氯甲烷和四氢呋喃中的任一种或任几种，所述碱溶液为碳酸氢钠水溶液、碳酸钠水溶液、碳酸钾水溶液和乙酸钾水溶液中的任一种。
  4. 根据权利要求1所述的制备方法，其特征在于，所述步骤b在有 机溶剂和强碱溶液的混合体系中完成，其中，反应温度为0～60℃。
  5. 根据权利要求4所述的制备方法，其特征在于，所述有机溶剂为二甲亚砜、四氢呋喃、甲醇、乙醇、丙醇、异丙醇、丁醇、二氧六环和丙酮中的任一种或任多种，所述强碱溶液为氢氧化钾水溶液、氢氧化钠水溶液和氢氧化锂水溶液中的任一种。
  6. 根据权利要求1所述的制备方法，其特征在于，所述步骤c在有机溶剂中完成，所述有机溶剂为二氯甲烷、乙酸乙酯、乙腈、四氢呋喃、二氧六环、丙酮、乙醚、异丙醚和氯仿中的任一种或任多种。
  7. 根据权利要求1-6中任一项所述的制备方法，其特征在于，所述步骤a包括如下步骤：
    a1.将磷酸奥司他韦、碳酸氢钠、四氢呋喃以及水混合搅拌至澄清得到第一体系；
    a2.在0～4℃的冰浴条件下，向所述第一体系中加入二叔丁基二碳酸酯的四氢呋喃溶液后反应至少10小时得到第一溶液；
    a3.蒸干所述第一溶液中的有机相后，使用叔丁基甲基醚对所述第一溶液萃取得到有机相溶液，将所述有机相溶液旋蒸至干得到所述化合物2。
  8. 根据权利要求7所述的制备方法，其特征在于，所述步骤b包括如下步骤：
    b1.将所述化合物2、甲醇和氢氧化钠水溶液混合搅拌得到第二溶液；
    b2.通过减压旋蒸去除所述第二溶液中的甲醇，之后加入水和叔丁基甲基醚洗涤得到水相溶液；
    b3.使用盐酸将所述水相溶液的pH值调至酸性直至析出化合物3。
  9. 根据权利要求8所述的制备方法，其特征在于，所述步骤b1在0～60℃搅拌至少一小时，所述步骤b3在0～4℃的冰浴条件下进行并将pH值调整至2。
  10. 根据权利要求8或9所述的制备方法，其特征在于，所述步骤c包括如下步骤：
    c1.向乙酸乙酯中通入氯化氢气体得到第二体系；
    c2.向所述第二体系中加入所述化合物3并加热至回流；
    c3.将所述第二体系降温后反应直至析出奥司他韦羧酸盐酸盐4。
  11. 根据权利要求10所述的制备方法，其特征在于，所述步骤c1在0～4℃的冰浴条件下进行，所述步骤c2在撤去冰浴并加热至回流后反应0.5～3小时，所述步骤c3中的所述第二体系的温度降到20～25℃并反应至少10小时。
  12. 根据权利要求11所述的制备方法，其特征在于，所述步骤a2中的反应时间为10～12小时，所述步骤b1中的搅拌时间为1～2小时，所述步骤c3中的反应时间为10～12小时。
  13. 奥司他韦羧酸盐酸盐雾化剂的制备方法，其特征在于，通过权利要求1至12中任一项所述的制备方法获得奥司他韦羧酸盐酸盐后，还包括如下步骤：
    i.制备奥司他韦羧酸盐酸盐与渗透压调节剂的混合液，其中，所述奥司他韦羧酸盐酸盐的含量为5～200mg；
    ii.加入pH缓冲剂将所述步骤i中的混合液的pH值调节至3.5～8.5得到奥司他韦羧酸盐酸盐雾化剂。
  14. 根据权利要求13所述的制备方法，其特征在于，所述奥司他韦羧酸盐酸盐雾化剂中含有0～2％质量百分比的表面活性剂。
  15. 根据权利要求14所述的制备方法，其特征在于，所述奥司他韦羧酸盐酸盐雾化剂被加工为冻干粉或者胶囊或者片剂。
PCT/CN2017/000426 2016-07-28 2017-07-10 奥司他韦羧酸盐酸盐及其雾化剂的制备方法 WO2018018851A1 (zh)

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