JP6516576B2 - Process for the preparation of (3R, 4S) -1- (4-fluorophenyl)-[3 (S) -hydroxy-3- (4-fluorophenyl) propyl]-[4- (phenylmethoxy) phenyl] -2-azetidinone - Google Patents

Description

  The present invention relates to ezetimibe (chemical name: (3R, 4S) -1- (4-fluorophenyl)-[3 (S) -hydroxy-3- (4-fluorophenyl) propyl]-(4-hydroxyphenyl)- (3R, 4S) -1- (4-Fluorophenyl)-[3 (S) -hydroxy-3- (4-fluorophenyl) propyl]-[4- (phenylmethoxy), a synthetic intermediate of 2-azetidinone) 1.) Phenyl] -2-azetidinone relates to a novel process of preparation.

  Following formula (4)

(3R, 4S) -1- (4-fluorophenyl)-[3 (S) -hydroxy-3- (4-fluorophenyl) propyl]-(4-hydroxyphenyl) -2-azetidinone (hereinafter referred to as Ezetimibe is also known as a therapeutic agent that selectively inhibits absorption of biliary and dietary cholesterol in the small intestine and lowers cholesterol in blood. Since ezetimibe used as such a therapeutic agent is desired to have a very high purity, it is extremely important to suppress the formation of impurities in the manufacturing process.

  As a manufacturing method of ezetimibe, following formula (2)

(3R, 4S) -1- (4-fluorophenyl)-[3-oxo-3- (4-fluorophenyl) propyl]-[4- (phenylmethoxy) phenyl] -2-azetidinone (hereinafter referred to as (Also referred to as a benzyl-protected keto compound) by asymmetric reduction from the following formula (3)

(3R, 4S) -1- (4-Fluorophenyl)-[3 (S) -hydroxy-3- (4-fluorophenyl) propyl]-[4- (phenylmethoxy) phenyl] -2-azetidinone designated There is known a method of synthesizing (hereinafter also referred to as benzyl protected) and subsequently preparing the benzyl protected by hydrogenation reaction in the presence of a catalytic amount of palladium carbon.

  And, as for the method of the above-mentioned asymmetric reduction reaction, for example, Patent Document 1 discloses a benzyl-protected keto compound and the following formula (1)

(R is any alkyl group or allyl group.)
A method is disclosed in which a compound represented by (hereinafter, also referred to as a CBS catalyst) is dissolved in tetrahydrofuran (hereinafter, also referred to as THF), and a borane dimethyl sulfide complex is added and reacted to obtain a benzyl protected product. Further, Patent Document 2 describes a method in which a CBS catalyst and a borane dimethyl sulfide complex are dissolved in THF, and a benzyl-protected keto compound is subsequently added and reacted to form a benzyl-protected compound. Then, Patent Document 3 describes a method of performing an asymmetric reduction reaction using a microorganism. Further, Patent Document 4 describes a method of performing an asymmetric reduction reaction using a ruthenium catalyst having an asymmetric ligand and hydrogen gas.

Patent 2803908 WO 2010/113182 pamphlet Patent 3679715 WO 2007/144780 pamphlet

  When the present inventor manufactured ezetimibe based on the conditions of the above-mentioned patent documents, with the method of patent document 1, following formula (5) is produced as a by-product

Were produced in large amounts, the optical purity of the protected benzyl compound was low, and the optical purity of ezetimibe obtained by deprotection was also low. Moreover, in the method described in Patent Document 2, high stereoselectivity can be obtained, but as a by-product, the following formula (6)

(3R, 4S) -1- (4-fluorophenyl) -2-hydroxy- (3 (S) -hydroxy-3-phenylpropyl)-(4-hydroxyphenyl) azetidine (hereinafter also referred to as a diol form) ) Are produced in large amounts, and the impurities can be removed by crystallization, but the yield of the benzyl protected substance is greatly reduced. And in the method of patent documents 3 and 4, since special facilities are required for manufacture, it is not suitable for industrialization.

  Therefore, an object of the present invention is to provide a method for producing a benzyl-protected compound by asymmetric reduction reaction of a benzyl-protected keto compound, wherein the high-purity benzyl-protected compound is reduced in the amount of optical isomers and diols. To provide a method of manufacturing.

  In order to solve the above-mentioned subject, the present inventor diligently studied about the method of asymmetric reduction reaction. As a result, when carrying out the asymmetric reduction reaction using borane in the presence of CBS catalyst, the CBS catalyst and a portion of the borane in the amount used are premixed, followed by addition of a benzyl-protected keto, and then the remaining By adding borane and allowing the reaction to proceed, surprisingly, a highly pure benzyl-protected compound having high stereoselectivity and less optical isomers is efficiently obtained without an increase in the amount of diol formed. Was found to be

  It was speculated that the reason for the increase in the optical isomer was that the benzyl-protected keto form was present in excess relative to the CBS catalyst in the reaction system, and the reduction reaction was proceeding without the aid of the catalyst. Moreover, it was speculated that the reason for the increase in the diol form was that the reduction reaction proceeded in the presence of an excess of borane relative to the benzyl-protected keto form in the reaction system, and the reduction was excessive. Therefore, in the initial stage of the reaction, a small excess of borane exists with respect to the benzyl-protected keto, that is, the reaction is performed by adding the benzyl-protected keto to a solution in which the CBS catalyst and a portion of the borane used are mixed beforehand. In the latter stage of the reaction, the benzyl protected keto is sufficiently consumed, and the reaction is allowed to proceed by adding borane in a state where the benzyl protected keto is not in excess with respect to the CBS catalyst. I believe that I could suppress the generation.

  Further, as a result of further investigation by the present inventor, it has been found that the reducing agent borane exhibits equivalent reactivity regardless of whether it is dimethyl sulfide complex or THF complex, and the present invention has been completed.

That is, the present invention provides an asymmetric reduction reaction of a benzyl-protected keto compound using borane in the presence of a catalytic amount of CBS catalyst to produce a benzyl protected compound, wherein one of the amounts of CBS catalyst and borane used is A method for producing a protected benzyl compound, which comprises adding a benzyl-protected keto compound to a reaction system in which a portion is present to carry out asymmetric reduction reaction, and then adding the remainder of borane to reprogress the asymmetric reduction reaction. and after producing the benzyl protected compound with said manufacturing process, the resulting benzyl protected form, the presence of a palladium carbon catalyst amount, a production method of ezetimibe for producing ezetimibe was deprotected by hydrogenation.

  According to the present invention, the asymmetric reduction reaction of benzyl-protected keto compound is carried out using borane in the presence of CBS catalyst to produce a benzyl protected product, wherein a part of the amount of CBS catalyst and borane used is previously By mixing, followed by addition of benzyl-protected keto, and then adding the remainder of borane to allow the reaction to proceed, the efficiency is reduced, particularly the high purity benzyl protected with reduced optical isomers and diol. Can be produced with good yield. In addition, high purity ezetimibe can be efficiently produced by deprotecting the benzyl protected product to produce ezetimibe.

  In the method of the present invention, the asymmetric reduction reaction of a benzyl-protected keto compound is carried out using borane in the presence of a CBS catalyst to partially mix the CBS catalyst and the amount of borane used in the method for producing a benzyl protected compound. Subsequently, a benzyl-protected keto compound is added to a reaction system in which a CBS catalyst and a part of the amount of borane used are present, and then the remainder of the borane is added to proceed the reaction. .

  In the present invention, in order to carry out the method for producing a benzyl protected compound, a benzyl protected keto compound is used as a raw material, and a borane which is a reducing agent is added in divided portions before and after addition of the benzyl protected keto compound in the presence of a CBS catalyst. As a result, by performing asymmetric reduction, the amount of generation of impurities is suppressed, and a highly protected benzyl protector with high optical purity can be obtained. Furthermore, alcohol and dilute acid are added to the reaction solution to stop the reaction, and if necessary, an extraction solvent is added to obtain an organic layer from which borane has been removed by liquid separation operation, and the organic layer is exchanged with an appropriate solvent. Then, by precipitating crystals of the protected benzyl compound, the protected benzyl compound can be effectively obtained as crystals of higher purity in which the content of the diol and the optical isomer is further reduced, which is preferable.

  That is, in the present invention, a complex formation step of mixing a part of the amount of borane used with the CBS catalyst, a primary reaction step of adding a benzyl-protected keto compound to the solution obtained by the complex formation step, and the remaining portion of borane Add a second reaction step to make the reaction proceed again, stop the reaction by adding alcohol and dilute acid, then extract the organic layer, replace the organic layer obtained in the extraction step with an appropriate solvent It is the most preferable embodiment that the precipitation step of crystallizing the benzyl protected product be continuously performed after the reaction. Hereinafter, the complex formation step, the primary reaction step, the secondary reaction step, the extraction step, and the precipitation step will be described in order.

Complex formation process
The complex formation step is a step of mixing the CBS catalyst and borane in a reaction solvent to obtain a solution containing a reactive species.

(CBS catalyst)
The CBS catalyst used in the present invention has the following formula (1)

(R is an alkyl group or an allyl group.)
It is a compound shown by these, and should just be R body. The substituent on the boron atom is not particularly limited and is selected from any alkyl group or allyl group, preferably a linear alkyl group, and more preferably a methyl group.

  The CBS catalyst may be in the solid state or in the form of a solution in a solvent. When used as a solid, the crystalline form thereof is not particularly limited, and may be in the form of crystals, amorphous, or a mixture thereof as long as it dissolves in the reaction solvent. In addition, the form of the CBS catalyst is not particularly limited, and may be a powder, a lump, or a mixed form thereof. In addition, the object may be an anhydride, and may be a wet substance containing a reaction solvent used in the present complex formation step. In addition, other solvents may be included as long as the asymmetric reduction reaction is not affected. When a CBS catalyst is used as a solution, a solution dissolved in an aromatic hydrocarbon such as the following reaction solvent or toluene can be used. The concentration of the CBS catalyst when used as a solution is not particularly limited, but in consideration of operability and solubility, the amount of solvent is preferably 0.2 L or more and 5.0 L or less with respect to 1.0 mol of CBS catalyst.

  The amount of the CBS catalyst used in the asymmetric reduction reaction may be 0.05 mol or more and 0.30 mol or less, and 0.10 mol or more and 0.20 mol or less, with respect to 1.0 mol of the benzyl-protected keto compound. Is preferred. When the amount of CBS catalyst used is less than 0.05 mol with respect to 1.0 mol of benzyl-protected keto compound, stereoselectivity decreases, and when it exceeds 0.30 mol, the reaction activity becomes too high, and the amount of diol formed is Unfavorably because it increases.

(Boran)
In the present invention, THF complex, dimethyl sulfide complex and pyridine complex can be used as borane. In view of reactivity, it is preferable to use THF complex and dimethyl sulfide complex, and in consideration of stability, dimethyl sulfide complex is particularly preferable.

  The amount of borane added in the present complex formation step is a part of the amount of borane used in the asymmetric reduction reaction. The amount of borane used in the asymmetric reduction reaction, that is, the total amount of borane added may be 0.7 mol or more and 1.2 mol or less, and 0.7 mol or more with respect to 1.0 mol of benzyl-protected keto compound It is more preferably 1.1 mol or less, and still more preferably 0.75 mol or more and 1.0 mol or less. When the total amount of borane added is less than 0.7 mol with respect to 1.0 mol of benzyl-protected keto compound, the reaction is not completed and the benzyl-protected keto compound remains; It is not preferable because it increases and the yield decreases. The use amount of borane added in the present complex formation step is a part thereof, and it is sufficient if it is 0.40 mol or more and 0.65 mol or less, 0.50 mol or more with respect to 1.0 mol of benzyl-protected keto compound It is preferable that it is 0.65 mol or less. If the borane added in the present complex formation step is less than 0.40 mol with respect to 1.0 mol of the benzyl-protected keto compound, the reaction conversion ratio becomes less than 60% in the primary reaction step described later, and the remainder in the secondary reaction step described later When the addition of is added, the optical isomer increases, and when it is more than 0.65 mol, the amount of diol formed increases and the yield decreases, which is not preferable. The remainder is added in the secondary reaction step described later.

(Reaction solvent)
In the present invention, as the reaction solvent, an aprotic polar solvent or a halogenated hydrocarbon is used. Specifically, N, N-dimethylformamide, N, N-dimethylacetamide, THF, 1,4-dioxane as the aprotic polar solvent, dichloromethane, chloroform, 1,2-dichloroethane as the halogenated hydrocarbon In consideration of operability and reactivity, THF and dichloromethane are preferred, and THF is particularly preferred. These can be used alone or in combination of two or more.

  Further, in the present complex formation step, the amount of the reaction solvent used may be appropriately determined depending on the type of reaction solvent to be used, reaction conditions, and the like. In consideration of operability and reactivity, it is preferably 2 mL or more and 50 mL or less, more preferably 3 mL or more and 40 mL or less, and particularly preferably 4 mL or more and 30 mL or less, with respect to 1.0 g of benzyl protected keto compound preferable.

(Operating conditions of complex formation process)
In the present complex formation step, the method of complex formation by mixing CBS catalyst, borane and reaction solvent to obtain a reaction solution containing reactive species is not particularly limited, and CBS catalyst and borane are mixed in the reaction solvent. Just do it. Specifically, a CBS catalyst and a reaction solvent may be mixed, and borane may be added to a stirred place, or a borane and a reaction solvent may be mixed and a CBS catalyst added to a stirred place. Also good. In consideration of operability and stability of borane, a method of pre-mixing the CBS catalyst and the reaction solvent and then adding borane is preferable. Borane may be added as it is, or borane may be diluted and added with the reaction solvent. When borane is added after dilution with a reaction solvent, the concentration is not particularly limited, but considering the operability and reactivity, the amount of reaction solvent is 0.01 L or more and 10 L or less with respect to 1.0 mol of borane. It is preferable that the pressure be 0.05 L or more and 1 L or less. In the complex formation step, the complex formation temperature may be −30 ° C. or more and 30 ° C. or less, preferably −20 ° C. or more and 25 ° C. or less, in consideration of reactivity and stability of borane, and preferably −15 ° C. or more It is more preferable that the temperature is not higher than ° C. The complex formation time may be appropriately determined according to the progress of complex formation, and is usually 15 minutes or more and 2 hours or less.

  The solution containing the reactive species obtained in the present complex formation step is a homogeneous solution and can be used in the next primary reaction step without any post-treatment.

<Primary reaction process>
The primary reaction step is a step of introducing a benzyl-protected keto compound into a solution containing the reactive species obtained in the complex formation step and performing an asymmetric reduction reaction. The solution obtained in the present primary reaction step is also referred to as a primary reaction solution.

(Benzyl protected keto)
The benzyl-protected keto compound used in the present invention is not particularly limited, and those produced by known methods can be used. Specifically, the method described in Patent Document 1, that is, 4-fluorophenylmagnesium chloride and zinc chloride are mixed, a catalytic amount of tetrakistriphenylphosphine palladium is added, and the following formula (7)

Addition of 3-[(3R, 4S)-[1- (4-fluorophenyl)]-[4- (phenylmethoxy) phenyl] -2-azetidinone-3-yl] propionyl chloride represented by It can be manufactured by doing.

  The purity of the benzyl protected keto is not particularly limited. That is, the benzyl-protected keto compound obtained by the above method may be highly purified by a known method, or it may be a crude product not purified (crude benzyl-protected keto compound). When a crude product is used as a target substance, the crude product (purity determined by peak area ratio) measured by high performance liquid chromatography (HPLC) described in detail in the following examples has a purity of 80% or more It is preferably a body. In consideration of the purity and yield of the finally obtained ezetimibe crystals, the crude product having a purity of 85% or more is preferable, the crude product having a purity of 90% or more is more preferable, and the crude product having a purity of 95% or more is particularly preferable. preferable.

  The crystal form of the benzyl-protected keto compound is not particularly limited, as long as it is dissolved in the reaction solvent, and may be crystalline, amorphous, or a mixed form thereof. In addition, the form of the benzyl-protected keto is not particularly limited, and may be a powder, a lump, or a mixed form thereof. In addition, the object may be an anhydrous substance, and may be a wet substance containing a reaction solvent used in the present primary reaction step. In addition, other solvents may be included as long as the reaction is not affected.

(Conditions of primary reaction process)
The method for adding the benzyl-protected keto to the solution containing the reactive species obtained in the complex formation step in the primary reaction step is not particularly limited, and a solid benzyl-protected keto may be added. The solution dissolved in the reaction solvent used in the reaction step may be added dropwise. When the benzyl-protected keto compound is used as a solution, the amount of the reaction solvent used may be appropriately determined depending on the type of reaction solvent used, reaction conditions, and the like. Considering operability and reactivity, it is preferably 1 mL or more and 20 mL or less, more preferably 2 mL or more and 18 mL or less, and particularly preferably 3 mL or more and 15 mL or less, with respect to 1 g of benzyl-protected keto compound. The temperature of the primary reaction may be -30 ° C to 10 ° C in consideration of reactivity and stereoselectivity, preferably -20 ° C to 5 ° C, and -15 ° C to 0 ° C. Is more preferred.

  In the primary reaction step, the reaction is preferably carried out until the residual amount of the added benzyl-protected keto compound in the system is 10 to 40%. The reaction time may be 30 minutes or more, preferably 1 hour to 12 hours. When the reaction time of this primary reaction step is 30 minutes or less, the benzyl-protected keto compound is not sufficiently consumed, and when the reaction is allowed to proceed in the following second reaction step, the benzyl-protected keto compound is excessive to the CBS catalyst Being in the state of being present, the stereoselectivity is reduced.

<Secondary reaction process>
The secondary reaction step is a step in which the remainder of borane is added to the primary reaction solution obtained in the primary reaction step, and the asymmetric reduction reaction is allowed to proceed again to obtain a solution containing a benzyl protector. The solution obtained in this second reaction step is also referred to as a second reaction solution.

(Boran)
As the borane used in the present secondary reaction step, the same one as the complex formation step can be used. The amount of borane added in the second reaction step is the balance of borane, and in consideration of the amount of borane added in the complex formation step, the total amount with the amount of borane used in the second reaction step is The total amount of borane used in the asymmetric reduction reaction may be set. The total amount of borane used in the asymmetric reduction reaction may be 0.7 moles or more and 1.2 moles or less, as described above, with respect to 1.0 mole of the benzyl-protected keto compound, and 0.7 moles It is more preferable that it is 1.1 mol or less, and it is further more preferable that it is 0.75 mol or more and 1.0 mol or less.

(Conditions of secondary reaction process)
In the present secondary reaction step, a method for obtaining a secondary reaction solution containing a benzyl protected substance by adding borane to the primary reaction solution obtained in the primary reaction step is not particularly limited. The borane added to the primary reaction solution may be added as it is as in the complex formation step, or borane may be added by diluting the borane with the reaction solvent used in the complex formation step and the primary reaction step. When diluted and added with the reaction solvent, the concentration may be the same as that in the complex formation step. The temperature of the secondary reaction may be −30 ° C. or more and 10 ° C. or less, preferably −20 ° C. or more and 5 ° C. or less, and is −15 ° C. or more and 0 ° C. or less in consideration of reactivity and stereoselectivity. Is more preferred. The reaction time may be appropriately determined according to the desired reaction conversion rate, and in order to make the reaction conversion rate 99% or more in the range of the reaction temperature, it is usually 1 hour or more and 12 hours or less.

<Extraction process>
The extraction step is a step of adding an alcohol and a dilute acid to the secondary reaction solution obtained in the second reaction step to stop the reaction, adding an extraction solvent, and extracting the organic layer contained in the benzyl protector. is there.

(alcohol)
As the alcohol used in this extraction step, one having 1 to 4 carbon atoms and miscible with water can be used, and specifically, methanol, ethanol, 1-propanol, 2-propanol, t-butyl alcohol and the like can be mentioned. From the viewpoint of operability, methanol and ethanol are preferable, and methanol is particularly preferable. The amount of alcohol used in this extraction step may be appropriately determined according to the type of alcohol used and reaction conditions, and considering the operability and reactivity, 0.1 mL per 1.0 g of benzyl-protected keto compound used The volume is preferably 20 mL or more, more preferably 0.2 mL or more and 15 mL or less, and still more preferably 0.3 mL or more and 10 mL or less.

(Dilute acid)
As the dilute acid used in this extraction step, a solution obtained by dissolving a water-soluble organic acid and an inorganic acid in water can be used. Specifically as the acid to be dissolved, formic acid, acetic acid, propionic acid, oxalic acid can be used. Examples thereof include acids, organic acids such as tartaric acid, and inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and nitric acid. In consideration of operability, inorganic acids are preferred, and hydrochloric acid is particularly preferred. The concentration of the dilute acid used in this extraction step may be appropriately determined according to the type of acid used and reaction conditions, and in consideration of operability and reactivity, 0.0001 mol / L to 3.0 mol / L. It is more preferable that it is 0.005 mol / L or more and 2.0 mol / L or less, and still more preferable that it is 0.001 mol / L or more and 1.5 mol / L or less. The amount of dilute acid used in this extraction step is not particularly limited, but in consideration of operability, it is preferably 0.2 mL or more and 30 mL or less per 1.0 g of benzyl-protected keto compound used, 0.4 mL It is more preferable that it is 25 mL or less, and it is more preferable that it is 0.5 mL or more and 20 mL or less.

(Extraction solvent)
The extraction solvent used in this extraction step may be any solvent as long as it has high solubility of benzyl-protected substance and is not miscible with water. Specifically, acetic acid ester and aromatic hydrocarbon may be mentioned. Preference is given to using esters, in particular ethyl acetate.

  The amount of extraction solvent used in this extraction step may be appropriately determined according to the type of extraction solvent to be used, but in consideration of operability, it is 2 mL or more and 200 mL or less per 1 g of benzyl-protected keto compound used. And more preferably 4 mL or more and 150 mL or less.

(Conditions of extraction process)
In this extraction step, the temperature at which the alcohol is added to the secondary reaction solution obtained in the second reaction step may be such that the reaction solution does not bump due to hydrogen generated at the time of addition, specifically -30 ° C The temperature may be 10 ° C. or less, preferably −20 ° C. or more and 5 ° C. or less, and more preferably −15 ° C. or more and 0 ° C. or less. The time for stirring after addition of the alcohol is not particularly limited, but is usually 10 minutes or more and 60 minutes or less. In the main extraction step, the temperature at which alcohol is added to the secondary reaction solution and the diluted acid is added to the solution in which the reaction is stopped may be in the range where the reaction solution does not bump, specifically -30 ° C or higher The temperature may be 20 ° C. or less, preferably −20 ° C. or more and 15 ° C. or less, and more preferably −10 ° C. or more and 10 ° C. or less. The time for stirring after addition of the dilute acid is not particularly limited, but is usually 10 minutes or more and 60 minutes or less. After the alcohol and dilute acid are added to the secondary reaction solution, an extraction solvent is further added and mixed, and the benzyl protected substance is extracted into the organic layer. The temperature at which the organic layer containing the benzyl protective compound is extracted may be appropriately determined depending on the type, amount, etc. of the extraction solvent to be used, and may be 10 ° C. in consideration of operability, as long as the benzyl protective compound does not crystallize. The temperature is preferably 55 ° C. or less, and more preferably 15 ° C. or more and 50 ° C. or less.

<Deposition process>
The precipitation step is a step of crystallizing the benzyl protected compound dissolved in the solvent after exchanging the organic layer containing the benzyl protected compound obtained in the extraction step with a suitable solvent.

(Crystallization solvent)
The crystallization solvent used in the present precipitation step may be an alcohol having 1 to 4 carbon atoms, and in consideration of operability and yield, ethanol and 2-propanol are preferable, and 2-propanol is particularly preferable.

  The amount of the crystallization solvent used in the present precipitation step may be appropriately determined according to the type of the crystallization solvent used, but in consideration of the operability, 2 mL or more to 100 mL per 1 g of the benzyl-protected keto compound used. It is preferable that it is the following, and it is more preferable that they are 3 mL or more and 80 mL or less.

(Poor solvent)
In the present precipitation step, an aliphatic hydrocarbon may be added to the crystallization solvent as a poor solvent. As the aliphatic hydrocarbon, one having 5 to 8 carbon atoms can be used, preferably a linear aliphatic hydrocarbon, particularly preferably hexane and heptane.

  The amount of the poor solvent in the case of adding the poor solvent may be appropriately determined according to the type of the crystallization solvent to be used, but in consideration of operability, 1 part by volume or more relative to 10 parts by volume of the crystallization solvent The content is preferably 20 parts by volume or less, and more preferably 2 parts by volume or more and 15 parts by volume or less.

(Conditions of precipitation process)
In the present precipitation step, the solvent exchange may be carried out by distilling off the solvent of the organic layer obtained in the extraction step and then adding a crystallization solvent. The method for distilling off the solvent of the organic layer is not particularly limited, and it may be distilled by heating under normal pressure or may be distilled off under reduced pressure. It is preferable to carry out distillation under reduced pressure in consideration of operability and stability of the benzyl protected product. When distillation under reduced pressure is performed, the temperature is preferably 0 ° C. or more and 70 ° C. or less, more preferably 3 ° C. or more and 65 ° C. or less, and still more preferably 5 ° C. or more and 60 ° C. or less. After evaporation of the solvent of the organic layer, a crystallization solvent is added to the benzyl protected product obtained as a residue for solvent exchange.

  In this precipitation step, the benzyl-protected product precipitates as crystals after solvent exchange, but the precipitated benzyl-protected product may be subjected to solid-liquid separation as it is, and after heating to dissolve, it is cooled to recrystallize. Solid-liquid separation may be performed. In consideration of the operability and the purity of the obtained benzyl protector, it is preferable to heat and dissolve, and then to cool and to recrystallize.

  When recrystallization is carried out, the temperature for dissolving the protected benzyl compound may be appropriately determined according to the type and amount of the crystallization solvent to be used, but in consideration of operability, it is 60 ° C. or more and not more than the boiling point of the crystallization solvent C., and more preferably 65.degree. C. or more and 75.degree. C. or less.

  In the case of recrystallization, a poor solvent may be added to the crystallization solvent as a solvent at the time of solvent exchange. When a poor solvent is added, the order in which the poor solvent is added is not particularly limited, and may be added to the residue obtained by distilling off the solvent of the organic layer simultaneously with the crystallization solvent. The residue may be dissolved and then added. In consideration of the operability and the purity of the resulting benzyl-protected product, it is preferable to add a poor solvent after heating and dissolving the residue obtained by distilling off the solvent of the organic layer in a crystallization solvent.

  In the present precipitation step, the temperature at which the crystals of the benzyl protected form are precipitated may be appropriately determined depending on the type and amount of the crystallization solvent and the poor solvent used, and so long as the benzyl protected form crystallizes. In consideration of the properties, the temperature is preferably 10 ° C. or more and 60 ° C. or less, and more preferably 15 ° C. or more and 58 ° C. or less. In addition, the temperature for growing crystals may be appropriately determined depending on the type and amount of good and poor solvents to be used, etc., considering the operability, yield, purity of obtained crystals, etc., -20 ° C or more and 20 ° C or less Preferably. It is more preferable that it is -15 degreeC or more and 15 degrees C or less, and it is more preferable that it is -10 degreeC or more and 10 degrees C or less. The time for growing crystals is not particularly limited, but is usually 2 to 24 hours.

  The benzyl-protected product obtained in the present invention can be made ezetimibe by a known method, for example, hydrogenation in the presence of a catalytic amount of palladium carbon, and in this case, the crystals of the benzyl-protected product are not necessarily dried. It is not necessary to be, and it may be a wet body containing the solvent used in the present invention. The protected benzyl obtained according to the invention is of low isomer content and is of very high purity. Therefore, it is possible to efficiently produce ezetimibe with high purity and high purity, which can be used as a pharmaceutical, without performing excessive purification operation.

  EXAMPLES Hereinafter, the present invention will be described in detail by way of examples, but the present invention is not limited by these examples.

  In the present example, the measurement of the purity of ezetimibe and the amount of impurities of the defluorinated substance were performed by high performance liquid chromatography (HPLC) as follows. In the present invention, the volume of the solution is at 25 ° C.

<Method for measuring purity and impurity amount>
Apparatus: High-performance liquid chromatograph (manufactured by Waters).
Detector: Ultraviolet absorptiometric detector (manufactured by Waters).
Measurement wavelength: 230 nm.
Column: ZORBAX SB-C18, inner diameter 4.6 mm, length 150 mm (manufactured by Agilent Technologies).
Column temperature: constant temperature around 25 ° C.
Buffer solution: An aqueous solution in which 2.4 g of sodium dihydrogen phosphate is dissolved in 1000 mL of water is added with an aqueous sodium hydroxide solution to adjust the pH to 5.0.
Mobile phase A: buffer / acetonitrile = 800/200 (volume ratio).
Mobile phase B: buffer / acetonitrile = 200/800 (volume ratio).
Transfer of mobile phase: The mixing ratio of mobile phase A and mobile phase B is changed as shown in Table 1 to control concentration gradient.
Flow rate: 1.0 mL per minute.
Measurement time: 65 minutes.

  Under the above conditions, a peak is observed at about 22.2 minutes for the benzyl protected form, about 27.5 minutes for the benzyl protected keto form, about 18.1 minutes for the diol form and 8.9 minutes for ezetimibe. In the following examples and comparative examples, the purity or content of the compound is the ratio of the area value of the peak of each compound to the total area value of all peaks (excluding the peak derived from the solvent) measured under the above conditions is there.

<Method for measuring optical purity and isomer amount>
Apparatus: High-performance liquid chromatograph (manufactured by Waters).
Detector: Ultraviolet absorptiometric detector (manufactured by Waters).
Measurement wavelength: 230 nm.
Column: CHIRALCEL OD-H, inner diameter 4.6 mm, length 250 mm (manufactured by Daicel).
Column temperature: constant temperature around 25 ° C.
Mobile phase: ethanol / hexane = 50/950 (volume ratio).
Flow rate: 1.0 mL per minute
Measurement time 45 minutes.

  Under the above conditions, the benzyl protected is detected at 27.6 minutes and the R isomer at 24.0 minutes. In the following examples and comparative examples, the purity or content of the compound is the ratio of the area value of the peak of each compound to the total area value of all peaks (excluding the peak derived from the solvent) measured under the above conditions is there.

Production Example A 5-L three-necked flask equipped with a stirring blade and a thermometer is purged with nitrogen, 3-[(3R, 4S)-[1- (4-fluorophenyl)]-[4- (phenylmethoxy) phenyl] 280 g of 2-azetidinone-3-yl] propionic acid and 3000 mL of dichloromethane were added, mixed with stirring and dissolved. After 126 g of oxalyl chloride is added to the reaction solution and stirred at 25 ° C. for 8 hours, the solution is concentrated to dryness, dissolved in 700 mL of THF, and 3-[(3R, 4S)-[1- (4-fluorophenyl)]-[4 A THF solution of-(phenylmethoxy) phenyl] -2-azetidinone-3-yl] propionyl chloride was obtained. Attach a stirring blade and a thermometer to a 10 L three-necked flask, replace the inside of the flask with nitrogen, add 180 g of zinc chloride and 1320 mL of a 4-fluorophenylmagnesium bromide THF solution (concentration 1 mol / L), stir and mix, 0 It cooled to ° C. Add 76.1 g of tetrakis (triphenylphosphine) palladium, and add 3-[(3R, 4S)-[1- (4-fluorophenyl)]-[4- (phenylmethoxy) phenyl] -2-azetidinone-3- The THF solution of [I] propionyl chloride was added dropwise and stirred at the same temperature for 3 hours. After the temperature was raised to about 20 ° C., 1500 mL of dilute hydrochloric acid and 5000 mL of ethyl acetate were added to extract the organic layer. The obtained organic layer was washed with 1000 mL of 10% brine, and the organic layer was concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography to obtain 883 g of a benzyl protected keto compound.

Example 1
The inside of a 500 mL three-necked flask equipped with a stirring blade and a thermometer was purged with nitrogen, and 200 mL of THF and 1.11 g of CBS catalyst (0.1 equivalent to a benzyl protected keto) were charged and mixed with stirring. The reaction solution was cooled to −10 ° C., 1.83 g (0.6 equivalents relative to the benzyl protected keto) of dimethyl sulfide borane was added, and the mixture was stirred at the same temperature for 30 minutes. To the reaction solution was added 20.0 g of benzyl protected keto, and the mixture was stirred at the same temperature for 1 hour. While maintaining the temperature of the reaction solution, 0.37 g of borane (0.15 equivalents relative to the benzyl protected keto) was added, and the mixture was further stirred for 2 hours. At the reaction end point, the content of the protected by benzyl was 83.42%, and the content of the diol was 6.52%. To the reaction solution was added 20 mL of methanol, and the mixture was stirred for 30 minutes, 50 mL of 1 M hydrochloric acid was added, and the mixture was further stirred for 30 minutes. The reaction solution was heated to about 25 ° C., 100 mL of ethyl acetate was added, and the organic layer was extracted. The obtained organic layer was washed with 200 mL of 10% brine, and the organic layer was concentrated under reduced pressure. To the residue, 100 mL of 2-propanol was added, the mixture was heated to 75 ° C. to dissolve the solid, and 100 mL of heptane was added to the reaction solution. The reaction solution is cooled to about 2 ° C. to precipitate a solid, and the precipitated crystal is collected by filtration under reduced pressure, washed with a mixed solution of 20 mL of 2-propanol and 20 mL of heptane, and dried under reduced pressure. 71 g (benzyl protected form: purity 98.8%, diol content 0.47%, optical isomer content 0.99%) was obtained (yield 83.2%).

Example 2
In Example 1, 1.98 g (0.65 equivalents relative to the benzyl-protected keto) of dimethyl sulfide borane added in the complexing step and 0.47 g (benzyl protected keto) of dimethyl sulfide borane added in the second reaction step The same procedure was carried out except that the amount was changed to 0.15 equivalent), and the protected benzyl compound 16.05 g (benzyl protector: purity 98.1%, diol content 0.59%, optical isomer content) An amount of 0.91% was obtained (yield 79.6%). The content of the protected benzyl at the end of the reaction was 81.98%, and the content of the diol was 7.14%.

Example 3
In Example 1, 1.22 g (0.4 equivalents relative to a benzyl-protected keto) of dimethyl sulfide borane added in the complexing step and 1.22 g (benzyl protected keto) of dimethyl sulfide borane added in the second reaction step The same procedure was carried out except that the amount was changed to 0.4 equivalent), and 16.49 g of benzyl protected product (benzyl protected product: purity 99.0%, diol content 0.30%, optical isomer content) An amount of 1.13% was obtained (yield 82.1%). The content of the protected benzyl at the end of the reaction was 87.21%, and the content of the diol was 4.94%.

Example 4
In a 100 mL three-necked flask equipped with a stirring blade, a thermometer, and a condenser, 3.0 g of the benzyl protected material obtained in Example 1 is charged, 30 mL of 2-propanol is added, and mixed by stirring, palladium carbon 0.15 g Were dispersed. 1.11 g of formic acid and 0.38 g of ammonium formate were added to the reaction solution, and the mixture was stirred at about 40 ° C. for 3 hours. The reaction solution was filtered to remove insolubles, and 15 mL of water was added to the filtrate to precipitate a solid. The resulting slurry is cooled to 3 ° C. and stirred for 8 hours, and the precipitated crystals are collected by filtration under reduced pressure, washed with a mixture of 2 mL of 2-propanol and 1 mL of water, and dried under reduced pressure to give crude ezetimibe 2.0 g of ezetimibe (ezetimibe: purity 99.8%, optical isomer content 0.22%) was obtained. In a 100 mL three-necked flask equipped with a stirring blade, a thermometer, and a condenser, 2.0 g of crude ezetimibe is added, 20 mL of ethanol and 10 mL of water are added and mixed by stirring, and heated to 60 ° C. to dissolve the solid The The reaction solution is cooled to about 2 ° C. and stirred for 4 hours, and the precipitated crystals are collected by filtration under reduced pressure, washed with a mixture of 1.3 mL of ethanol and 0.7 mL of water, and dried under reduced pressure to give ezetimibe 1. 8 g (purity of ezetimibe 99.9%, optical isomer not detected) was obtained (yield 74.4%).

Comparative Example 1
In a 500 mL three-necked flask equipped with a stirring blade and a thermometer, replace with nitrogen, and 200 mL of THF, 1.11 g of CBS catalyst (0.1 equivalent to benzyl protected keto) and 20.0 g of benzyl protected keto are introduced. Stir mixed. The reaction solution was cooled to −10 ° C., 2.20 g of dimethyl sulfide borane (0.75 equivalents relative to the benzyl protected keto) was added, and the mixture was stirred at the same temperature for 8 hours. At the reaction end point, the content of the protected benzyl compound in the reaction mixture was 83.05%, and the diol content was 5.59%. To the reaction solution was added 20 mL of methanol, and the mixture was stirred for 30 minutes, 50 mL of 1 M hydrochloric acid was added, and the mixture was further stirred for 30 minutes. The reaction solution was heated to about 25 ° C., 100 mL of ethyl acetate was added, and the organic layer was extracted. The obtained organic layer was washed with 200 mL of 10% brine, and the organic layer was concentrated under reduced pressure. To the residue, 100 mL of 2-propanol was added, the mixture was heated to 75 ° C. to dissolve the solid, and 100 mL of heptane was added to the reaction solution. The reaction solution is cooled to about 2 ° C. to precipitate a solid, and the precipitated crystal is collected by filtration under reduced pressure, washed with a mixed solution of 20 mL of 2-propanol and 20 mL of heptane, and dried under reduced pressure. 39 g (benzyl protected form: purity 97.9%, diol content 0.42%, optical isomer content 13.99%) was obtained (yield 81.6%).

Comparative example 2
The inside of a 500 mL three-necked flask equipped with a stirring blade and a thermometer was purged with nitrogen, and 200 mL of THF and 1.11 g of CBS catalyst (0.1 equivalent to a benzyl protected keto) were charged and mixed with stirring. The reaction solution was cooled to −10 ° C., 2.20 g of dimethyl sulfide borane (0.75 equivalents relative to the benzyl protected keto) was added, and the mixture was stirred at the same temperature for 30 minutes. 20.0 g of benzyl protected keto was added to the reaction solution, and the mixture was stirred at the same temperature for 2 hours. At the reaction end point, the content of the protected by benzyl was 69.91% and the content of the diol was 12.79%. To the reaction solution was added 20 mL of methanol, and the mixture was stirred for 30 minutes, 50 mL of 1 M hydrochloric acid was added, and the mixture was further stirred for 30 minutes. The reaction solution was heated to about 25 ° C., 100 mL of ethyl acetate was added, and the organic layer was extracted. The obtained organic layer was washed with 200 mL of 10% brine, and the organic layer was concentrated under reduced pressure. To the residue, 100 mL of 2-propanol was added, the mixture was heated to 75 ° C. to dissolve the solid, and 100 mL of heptane was added to the reaction solution. The reaction solution is cooled to about 2 ° C. to precipitate solids, and the precipitated crystals are collected by filtration under reduced pressure, washed with a mixed solution of 20 mL of 2-propanol and 20 mL of heptane, and dried under reduced pressure to obtain benzyl protected product 13.3. 82 g (benzyl protected form: purity 98.0%, diol content 0.69%, optical isomer content 1.02%) was obtained (yield 68.8%).

Comparative example 3
The same procedure as in Example 4 was performed using the protected benzyl compound obtained in Comparative Example 1. Obtain 1.8 g (95% ezetimibe purity, 7.79% optical purity) as crude ezetimibe, and 1.4 g ezetimibe (99.7% ezetimibe, content of optical isomer 4.69%) ezetimibe (Yield 57.9%).

Claims (5)

Following equation (1) of the amount of catalyst

(R is any alkyl or allyl group)
Using borane in the presence of a compound represented by formula (2)

Asymmetry of (3R, 4S) -1- (4-fluorophenyl)-[3-oxo-3- (4-fluorophenyl) propyl]-[4- (phenylmethoxy) phenyl] -2-azetidinone as shown in The reduction reaction is carried out, and the following formula (3)

(3R, 4S) -1- (4-Fluorophenyl)-[3 (S) -hydroxy-3- (4-fluorophenyl) propyl]-[4- (phenylmethoxy) phenyl] -2-azetidinone designated (3R, 4S) -1- (4-fluorophenyl)-[3-oxo in a reaction system in which a portion of the compound represented by the above formula (1) and the amount of borane used is present in the method of producing The asymmetric reduction reaction is carried out by adding -3- (4-fluorophenyl) propyl]-[4- (phenylmethoxy) phenyl] -2-azetidinone, and then the remainder of borane is added to re- conduct the asymmetric reduction reaction. (3R, 4S) -1- (4-fluorophenyl)-[3 (S) -hydroxy-3- (4-fluorophenyl) propyl]-[4- (phenylmethoxy) fe characterized by advancing ] -2- azetidinone manufacturing method. Following equation (1) of the amount of catalyst

(R is any alkyl or allyl group)
And mixing a part of the amount of borane used to obtain a solution containing reactive species, complexing step to obtain a solution containing reactive species, (3R, 4S) -1- (4-fluorophenyl) in a solution containing reactive species A primary reaction step to obtain a primary reaction solution by adding-[3-oxo-3- (4-fluorophenyl) propyl]-[4- (phenylmethoxy) phenyl] -2-azetidinone and performing an asymmetric reduction reaction, Add the remaining part of borane to the primary reaction solution to make the asymmetric reduction reaction proceed again, to obtain the secondary reaction solution Secondary reaction process to obtain the secondary reaction solution, add alcohol and dilute acid to the secondary reaction solution to stop the reaction, extract solvent In addition, (3R, 4S) -1- (4-fluorophenyl)-[3 (S) -hydroxy-3- (4-fluorophenyl) propyl]-[4- (phenylmethoxy) phenyl] -2-azetidinone Extract the organic layer Process, (3R, 4S) -1- (4-fluorophenyl)-[3 (S) -hydroxy-3- (4-fluorophenyl) propyl]-[4- (phenylmethoxy) phenyl] -2-azetidinone (3R, 4S) -1- (4-fluorophenyl)-[3 (S) -hydroxy-3- (4-fluorophenyl) propyl]-[4- (phenylmethoxy) after solvent exchange of the organic layer containing it. The (3R, 4S) -1- (4-fluorophenyl)-[3 (S) -hydroxy-3- (4-fluoro) as claimed in claim 1, comprising a precipitation step which crystallizes phenyl] -2-azetidinone. Process for the preparation of phenyl) propyl]-[4- (phenylmethoxy) phenyl] -2-azetidinone.   The amount of borane used is (3R, 4S) -1- (4-fluorophenyl)-[3-oxo-3- (4-fluorophenyl) propyl]-[4- (phenylmethoxy) phenyl] -2-azetidinone 0.7 to 1.2 moles per 1.0 mole, and part of the amount of borane used is (3R, 4S) -1- (4-fluorophenyl)-[3-oxo-3 3. The method according to claim 1, wherein the amount is 0.40 to 0.65 moles per 1.0 mole of-(4-fluorophenyl) propyl]-[4- (phenylmethoxy) phenyl] -2-azetidinone. Production method.   The method according to any one of claims 1 to 3, wherein the reaction time for performing the asymmetric reduction reaction in the presence of a part of the amount of borane used is 30 minutes or more. A method according to any one of claims 1 to 4 wherein (3R, 4S) -1- (4-fluorophenyl)-[3 (S) -hydroxy-3- (4-fluorophenyl) propyl]-[4- The ( 3R, 4S) -1- (4-fluorophenyl)-[3 (S) -hydroxy-3- (4-fluorophenyl) propyl obtained after producing (phenylmethoxy) phenyl] -2-azetidinone ]-[4- (phenylmethoxy) phenyl] -2-azetidinone is deprotected by hydrogenation in the presence of a catalytic amount of palladium carbon, and the following formula (4)

A process for producing ezetimibe, which comprises producing ezetimibe shown by