JP6182183B2 - Method for producing duloxetine base and duloxetine hydrochloride - Google Patents

Description

  The present invention relates to a method for producing high-purity duloxetine base and duloxetine hydrochloride with reduced formation of optical isomers and degradation products.

  Duloxetine hydrochloride is one of the serotonin and noradrenaline reuptake inhibitors and is used to treat depression, depression, and pain associated with diabetic neuropathy. In Japan, it is marketed as Cymbalta (registered trademark) capsule. ing.

  Duloxetine hydrochloride is represented by the chemical name (S)-(+)-N-methyl-3- (1-naphthyloxy) -3- (2-thienyl) propylamine hydrochloride, and the structural formula is III).

前記デュロキセチン塩酸塩を製造する際の中間体として、デュロキセチン塩基が知られている（特許文献１）。また、特許文献２および特許文献３には、デュロキセチン塩基の改良された製造方法およびデュロキセチン塩酸塩の製造方法が開示されている。

Duloxetine base is known as an intermediate for producing the duloxetine hydrochloride (Patent Document 1). Patent Document 2 and Patent Document 3 disclose an improved method for producing duloxetine base and a method for producing duloxetine hydrochloride.

  The production schemes of typical duloxetine hydrochloride described in Patent Documents 1 to 4 are shown below.

すなわち、これまでに報告されている代表的なデュロキセチン塩酸塩の製造方法は、前記スキームに示すように、まず、工程１−２で、２−アセチルチオフェン、ジメチルアミン塩酸塩およびパラホルムアルデヒドとの反応により３−ジメチルアミノ−１−（２−チエニル）−１−プロパノンを得て、還元し，光学活性マンデル酸との塩形成によって（Ｓ）−（−）−Ｎ，Ｎ−ジメチル−３−（２−チエニル）−３−ヒドロキシプロピルアミンを得る。次いで、工程３で、Ｎ，Ｎ−ジメチル−３−（２−チエニル）−３−ヒドロキシプロピルアミンと１−フルオロナフタレンと反応させ、続く工程４で脱メチル化を行い、工程５で塩基性加水分解によるデュロキセチン塩基の調製を行う。そして、工程６において、デュロキセチン塩基に塩酸を加えて、デュロキセチン塩酸塩を得ることができる。

That is, a typical method for producing duloxetine hydrochloride that has been reported so far, as shown in the above scheme, first, in step 1-2, reaction with 2-acetylthiophene, dimethylamine hydrochloride and paraformaldehyde To 3-dimethylamino-1- (2-thienyl) -1-propanone, reduced, and salted with optically active mandelic acid to form (S)-(−)-N, N-dimethyl-3- ( 2-Thienyl) -3-hydroxypropylamine is obtained. Next, in step 3, N, N-dimethyl-3- (2-thienyl) -3-hydroxypropylamine is reacted with 1-fluoronaphthalene, followed by demethylation in step 4 and basic hydrolysis in step 5. Preparation of duloxetine base by degradation. And in process 6, duloxetine hydrochloride can be obtained by adding hydrochloric acid to duloxetine base.

  In Patent Document 1, Patent Document 2 and Patent Document 3, duloxetine carbamate is produced in step 4 by reaction with a chloroformate, preferably phenyl chloroformate or trichloroethyl chloroformate, and then in step 5, carbamate. A process for the production of duloxetine base by hydrolyzing the base in a base is disclosed. Patent Document 2 reports a process for producing duloxetine base by desorbing duloxetine carbamate in the presence of a mixture of zinc and formic acid, followed by hydrolysis in a base.

  Furthermore, as an improved method for converting duloxetine alkyl carbamate to duloxetine base and salts thereof, a method for producing duloxetine base using toluene and potassium hydroxide has been reported (Patent Document 4).

JP-A 63-185946 Japanese Patent Laid-Open No. 04-226948 Japanese Patent Laid-Open No. 07-188065 JP 2004-123596 A Special Table 2007-523213

  However, with respect to the known demethylation steps in Steps 4 and 5 described in the synthesis route of the above scheme, in the production methods described in Patent Documents 1 to 4, phenylchloroformate is not used for the production of duloxetine carbamate, which is an intermediate. Since mate or trichloroethyl chloroformate is used, there is a problem that in step 5, toxic phenol or trichloroethanol is produced. Furthermore, in patent document 2, since zinc which is a metal is used, when using it as a pharmaceutical raw material, a complicated refinement | purification process is needed and there exists a possibility that a metal may remain.

  In the method described in Patent Document 5, since the solubility of potassium hydroxide in toluene is low, the conversion rate to the target intermediate duloxetine base is low, and a high temperature is required for the reaction to proceed. It is known that there is. Therefore, although it was necessary to heat the reaction mixture to the reflux temperature of toluene, racemization and generation of decomposition products caused by the heating were problems.

  Therefore, the present condition is that the further improvement for manufacture of highly purified duloxetine base is calculated | required.

  The present invention solves these problems, and provides a method for producing highly pure duloxetine base and duloxetine hydrochloride that suppresses toxic by-products and suppresses formation of optical isomers and degradation products. For the purpose.

  According to one embodiment of the present invention, the following formula (II)

で表されるデュロキセチン塩基の製造方法は、
下記式（Ｉ）

The method for producing duloxetine base represented by
Formula (I)

（式中、ＲはＣ１〜Ｃ４のアルキル基を表す）
で表されるデュロキセチンアルキルカルバメート、水酸化カリウムおよびトルエンを低級アルコールの存在下に混合する工程、及び
得られた混合液を加熱して反応させ、反応中に一部の溶媒を留去する工程を含むことを特徴とする。

(Wherein R represents a C1-C4 alkyl group)
A step of mixing duloxetine alkyl carbamate represented by the formula: potassium hydroxide and toluene in the presence of a lower alcohol; and a step of heating and reacting the resulting mixture to distill off part of the solvent during the reaction. It is characterized by including.

  In the production method, it is preferable that the potassium hydroxide is dissolved in the lower alcohol and then mixed with a toluene solution in which the duloxetine alkyl carbamate is dissolved.

  In the formula (I), R is preferably ethyl.

  Furthermore, the lower alcohol is preferably ethanol.

  Moreover, in the said manufacturing method, it is preferable that the said reaction temperature is 95 to 100 degree | times.

  The method for producing duloxetine hydrochloride according to another aspect of the present invention includes converting duloxetine base obtained by the above-described production method into duloxetine hydrochloride.

  Furthermore, in the manufacturing method of the said duloxetine hydrochloride, it is preferable to convert into the said duloxetine hydrochloride using the mixed solvent containing methyl ethyl ketone and methanol.

  According to the present invention, there is provided a method for producing a highly pure duloxetine base and duloxetine hydrochloride that suppresses toxic by-products and suppresses formation of optical isomers and degradation products, which is superior to conventional ones. Can do.

  According to one embodiment of the present invention, the following formula (II)

で表されるデュロキセチン塩基の製造方法は、
下記式（Ｉ）

The method for producing duloxetine base represented by
Formula (I)

（式中、ＲはＣ１〜Ｃ４のアルキル基を表す）
で表されるデュロキセチンアルキルカルバメート、水酸化カリウムおよびトルエンを低級アルコールの存在下に混合する工程、及び
得られた混合液を加熱して反応させ、反応中に一部の溶媒を留去する工程を含むことを特徴とする。

(Wherein R represents a C1-C4 alkyl group)
A step of mixing duloxetine alkyl carbamate represented by the formula: potassium hydroxide and toluene in the presence of a lower alcohol; and a step of heating and reacting the resulting mixture to distill off part of the solvent during the reaction. It is characterized by including.

  According to such a production method, it is possible to provide a highly pure duloxetine base by suppressing toxic by-products and suppressing formation of optical isomers and decomposition products.

  This is considered to be due to the following reason. As described above, a production method using potassium hydroxide and toluene is widely known for the conversion of duloxetine alkyl carbamate to duloxetine base as in Step 5 in the above scheme. In the present invention, in order to further improve the low solubility of potassium hydroxide in toluene in this reaction system, the reaction solution is made uniform by interposing a lower alcohol. Thereby, the conversion rate from duloxetine alkyl carbamate to duloxetine base can be improved. However, since the toluene-lower alcohol mixed solvent forms an azeotropic mixture, the reflux temperature is lower than that of a single solvent of toluene. Therefore, heating is performed during the reaction to raise the temperature inside the reaction system, and a part of the reaction solvent is distilled off, so that the reaction proceeds more quickly than in the conventional method, and the optical isomers and decomposition products are obtained. It is thought that the manufacture which suppressed the production | generation of can be performed.

  Hereinafter, although the embodiment concerning the present invention is described more concretely, the present invention is not limited to these.

  The method for producing duloxetine base of the present embodiment includes a step of mixing duloxetine alkyl carbamate represented by the formula (I), potassium hydroxide and toluene in the presence of a lower alcohol, and heating the mixture to react. And a step of distilling off a part of the solvent during the reaction. If the said process is included, there will be no limitation in particular about another process.

  The duloxetine alkyl carbamate of this embodiment is preferably (S) -duloxetine alkyl carbamate, and the duloxetine-base is preferably (S) -duloxetine base.

In the present embodiment, the duloxetine alkyl carbamate represented by the formula (I) can be obtained by a known synthesis method. For example, duloxetine alkyl carbamate can be obtained by steps 1-4 shown in the above scheme. Specifically, first,
(S)-(-)-N, N is obtained by reducing and optically resolving 3-dimethylamino-1- (2-thienyl) -1-propanone obtained by the reaction of 2-acetylthiophene and dimethylamine hydrochloride. -Dimethyl-3- (2-thienyl) -3-hydroxypropylamine is obtained (step 1-2). Next, N, N-dimethyl-duloxetine is obtained by reaction with 1-fluoronaphthalene (step 3). Subsequently, the duloxetine alkyl carbamate represented by the formula (I) can be produced by reaction with the corresponding alkyl chloroformate (step 4).

  In the duloxetine alkyl carbamate represented by the formula (I) used in the present embodiment, in the formula (I), R is a C1-C4 alkyl group. The alkyl group may be linear or branched and is preferably at least one selected from the group consisting of a methyl group, an ethyl group, an n-propyl group, and an isopropyl group. More preferably, the alkyl group is an ethyl group.

  When the R group is an alkyl group as described above, it is possible to suppress the production of carbamate-derived alcohol by-products that have been generated by the conversion of duloxetine alkyl carbamate to duloxetine base in the conventional production method. Since highly toxic by-products such as phenol produced by conventional production methods are not preferable, the ability to suppress such by-products is considered in consideration of environmental considerations and use as a pharmaceutical raw material. Very advantageous.

  The potassium hydroxide used in the present embodiment may be a solid (granule) or a solution, but when dissolving the solid, it may take a long time to dissolve. More preferably, the lower alcohol solution in which the potassium hydroxide is dissolved is mixed with the toluene solution in which the duloxetine alkyl carbamate is dissolved.

  The usage-amount of potassium hydroxide in the manufacturing method of this embodiment is 2-10 times amount normally with respect to the said duloxetine alkyl carbamate, Preferably, it is 4-6 times amount. If the amount of potassium hydroxide is less than 2 times the amount of the duloxetine alkyl carbamate, the reaction rate may decrease. On the other hand, if the amount exceeds 10 times the amount of ethanol for dissolving potassium hydroxide. This increases the production efficiency and lowers the production efficiency.

  Although the lower alcohol used by this embodiment is not specifically limited, For example, it is a C1-C4 lower alcohol. Preferably, it is at least one selected from the group consisting of methanol, ethanol, 1-propanol, 2-propanol, and butanol, and more preferably ethanol.

  When the lower alcohol is ethanol, there is an advantage that the boiling point is higher than that of methanol and the solubility of potassium hydroxide is higher than that of propanol. Further, when duloxetine ethyl carbamate is used as a raw material, there is an advantage that the reaction is not complicated because the raw material and the product in the transesterification reaction as a side reaction have the same structure.

  The amount of the lower alcohol used in the production method of the present embodiment is usually 2 to 10 times, preferably 3 to 6 times the amount of the duloxetine alkyl carbamate. When the amount of the lower alcohol is less than twice the amount of the duloxetine alkyl carbamate, it is difficult to control the exotherm when dissolving the potassium hydroxide. On the other hand, when the amount exceeds 10 times, this is reduced during the reaction. It takes a long time to distill off, which is not preferable because the entire process time is extended.

  Moreover, in the manufacturing method of this embodiment, the usage-amount of the toluene which dissolves the said duloxetine alkyl carbamate is 2-10 times amount normally with respect to the said duloxetine alkyl carbamate, Preferably it is 3-6 times amount. If the amount of toluene is less than twice the amount of the duloxetine alkyl carbamate, it may be difficult to raise the temperature inside the reaction system when the solvent is distilled off. The reaction rate may decrease.

  In the production method of the present embodiment, the toluene solution in which the potassium hydroxide, the lower alcohol, and the duloxetine alkyl carbamate are dissolved is mixed, or the lower alcohol solution in which the potassium hydroxide is dissolved is mixed with the duloxetine alkyl. Mix with toluene solution with carbamate dissolved.

  Next, at least a part of the reaction solvent is distilled off while reacting by heating the mixed solution obtained above. Thereby, the temperature inside the reaction system rises, and the reaction is considered to proceed promptly.

  The means for partly distilling off the reaction solvent is not particularly limited, but can be carried out, for example, by using a Dean-Stark apparatus. The amount of distillation can be adjusted as appropriate by opening and closing the cock.

  The heating of the mixed solution in the present embodiment is not particularly limited as long as the temperature is such that the reaction proceeds, but the heating is performed so that the reaction temperature is 90 to 105 ° C, preferably about 95 to 100 ° C. It is preferable to do. When the reaction temperature is lower than 90 ° C., the reaction rate becomes slow, and when the internal temperature exceeds 110 ° C., optical isomers and decomposition products may increase.

  Although the heating time varies depending on the heating temperature and the like, in this embodiment, since the reaction proceeds promptly after reaching the above temperature, the heating is usually performed for about 1 to 6 hours, preferably 2 to 4 hours. . The progress of the reaction is preferably followed by HPLC or the like, and the reaction is preferably stopped when the disappearance of the raw material duloxetine alkyl carbamate is confirmed.

  In the present embodiment, as described above, by evaporating a part of the reaction solution (solvent), the temperature of the reaction solution can be raised to promote the progress of the reaction. After the temperature of the reaction solution has reached the reaction temperature, the frequency and the amount of distillation when the solvent is further distilled off can be appropriately determined each time according to the temperature change. Further, when the temperature drops due to the precipitation of inorganic salt with the progress of the reaction, the solvent may be distilled off again.

  The above-described reaction of this embodiment can be stopped by finishing the heating. The obtained reaction solution is cooled, and then the product is extracted into an organic layer according to a conventional method and purified to obtain duloxetine base represented by the above formula (II). Furthermore, the obtained crude product of duloxetine base can be converted into a salt according to a conventional method without purification.

  The duloxetine base represented by the above formula (II) obtained by the production method of the present embodiment can be led to duloxetine hydrochloride by a known method or the like. As a specific example, duloxetine hydrochloride can be obtained by adding hydrochloric acid or HCl ethyl acetate solution to the toluene solution or ethyl acetate solution of duloxetine base (IIa) and filtering the precipitated crystals. .

  Preferred examples of the solvent used for hydrochloric acid chlorination in the present embodiment include methyl ethyl ketone, methanol, toluene, and mixed solvents thereof.

  Using the duloxetine base and duloxetine hydrochloride obtained as described above, a pharmaceutical composition containing an appropriate amount thereof as an active ingredient can be prepared. The prepared pharmaceutical composition is used for the treatment and / or prevention of pain associated with depression / depressive state and diabetic neuropathy.

  The present invention will be described more specifically with reference to the following examples. However, the scope of the present invention is not limited to these examples.

（実施例１）デュロキセチン塩基（ＩＩａ）の製造
公知の方法（上述のスキームの工程１〜４）によって前記式（Ｉｂ）で示されるデュロキセチンアルキルカルバメート合成した。具体的には、２−アセチルチオフェン（６３．１ｇ；０．５ｍｏｌ）、ジメチルアミン塩酸塩（５３．０ｇ；０．６５ｍｏｌ）、パラホルムアルデヒド（１９．８ｇ；０．２２ｍｏｌ）およびエタノール（８０ｍｌ）中の１２Ｎ塩酸（１ｍｌ）とを反応させて３−ジメチルアミノ−１−（２−チエニル）−１−プロパノン塩酸塩を得て、水素化ホウ素ナトリウムを用いて還元、光学活性マンデル酸により分割し、光学活性な（Ｓ）−（−）−Ｎ，Ｎ−ジメチル−３−（２−チエニル）−３−ヒドロキシプロピルアミンを得た。次に、１−フルオロナフタレンと水素化ナトリウムとの反応により、Ｎ，Ｎ−ジメチル−デュロキセチンを得た。続いて、対応するアルキルクロロホルメート（４．６ｍｌ；４８．５ｍｍｏｌ）との反応により、前記式（Ｉｂ）で示されるデュロキセチンアルキルカルバメートを得た。

Example 1 Production of duloxetine base (IIa) A duloxetine alkyl carbamate represented by the above formula (Ib) was synthesized by a known method (steps 1 to 4 in the above-mentioned scheme). Specifically, in 2-acetylthiophene (63.1 g; 0.5 mol), dimethylamine hydrochloride (53.0 g; 0.65 mol), paraformaldehyde (19.8 g; 0.22 mol) and ethanol (80 ml) Of 12N hydrochloric acid (1 ml) to give 3-dimethylamino-1- (2-thienyl) -1-propanone hydrochloride, reduced with sodium borohydride, resolved with optically active mandelic acid, Optically active (S)-(−)-N, N-dimethyl-3- (2-thienyl) -3-hydroxypropylamine was obtained. Next, N, N-dimethyl-duloxetine was obtained by the reaction of 1-fluoronaphthalene and sodium hydride. Subsequently, a duloxetine alkyl carbamate represented by the formula (Ib) was obtained by reaction with the corresponding alkyl chloroformate (4.6 ml; 48.5 mmol).

  To a toluene solution (10 mL) of the obtained duloxetine ethyl carbamate (Ib) (2.5 g; 6.7 mmol), an ethanol solution (10 mL) of potassium hydroxide (purity 87%, 2.16 g; 33.5 mmol) was added at room temperature. Added at. The mixture was heated to reflux at 85-90 ° C., and then the solvent was distilled off until the internal temperature reached 100 ° C. Further, while repeating the evaporation of the solvent, the temperature was maintained in the range of 95-100 ° C., and the mixture was stirred for 2 hours. After cooling to room temperature, water (10 mL) and ethyl acetate (10 mL) were added, and the resulting organic layer was washed with water (20 mL). Drying over sodium sulfate, filtering and concentration to dryness afforded the title compound in 1.96 g (yield: 98.4%, optical isomer: 0.16%).

¹ H-NMR (400 MHz, DMSO-d6): 8.23-8.20 (m, 1H), 7.86-7.82 (m, 1H), 7.53-7.49 (m, 2H) , 7.44-7.41 (m, 2H), 7.33 (t, 1H), 7.21 (dd, 1H), 7.05 (d, 1H), 6.97 (dd, 1H), 5.99 (t, 1H), 2.62 (2H, t) 2.26 (3H, s), 2.36-2.29 (m, 1H), 2.12 to 2.03 (m, 1H) )
(Reference Example) Production of duloxetine base by conventional method Toluene solution (20 mL) of duloxetine ethyl carbamate (Ib) (2.5 g; 6, 7 mmol) in the same lot as Example 1 was added with potassium hydroxide (purity 87%, 4. 8 g, 74.4 mmol) was added at room temperature. The mixture was stirred and subsequently refluxed for 4 hours. After cooling, 30 mL of water is added followed by 20 mL of toluene and the resulting organic phase is washed with water (3 × 20 mL), dried over sodium sulfate, filtered and concentrated to dryness. 24 g of an oily product was obtained (yield: 62.3%, optical isomer: 7.67%). The obtained product showed the same NMR spectrum as in Example 1.

(Evaluation test)
Each duloxetine base thus obtained was evaluated by the following high performance liquid chromatography (HPLC) analysis.

(1) Confirmation of disappearance of raw materials and content of each related substance Using the following conditions, each peak area percentage was measured by an automatic integration method by a liquid chromatographic method.

Detector: UV absorption photometer (230nm)
Column: A stainless tube having an inner diameter of 4.6 mm and a length of 15 cm is packed with octadecylsilylated silica gel for liquid chromatography having a particle diameter of 3.5 μm (column used: Agilent ZORBAX SB-C8).
Column temperature: constant temperature around 40 ° C. Mobile phase: 2.9 g (1.7 mL) of phosphoric acid is added to 900 mL of water, and sodium hydroxide reagent solution is added to adjust to pH 2.5. Add water to this solution to make 1000 mL, and add 9.4 g of sodium 1-hexanesulfonate. To 580 mL of this solution, 140 mL of 1-propanol and 280 mL of acetonitrile are added.
Flow rate: About 1 mL / min

(2) About optical isomers Using the following conditions, each peak area percentage is measured by an automatic integration method by liquid chromatography, and the content (%) of (R) isomers, which are optical isomers, is calculated by the following formula. Calculated.

Detector: UV absorption photometer (220nm)
Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 15 cm is packed with 5 μm of a cellulose derivative-bonded silica gel for liquid chromatography (column used: CHIRAL ART Cellulose-C).
Column temperature: Constant temperature around 40 ° C. Mobile phase: 85 g of perchloric acid is diluted with 2000 mL of distilled water, and 40 g of sodium hydroxide is added to adjust the pH to 2.1. Add 450 mL of acetonitrile to 550 mL of this liquid. Flow rate: About 1 mL / min

Ｑ_Ｒ：Ｒ体のピーク面積百分率
Ｑ_Ｓ：Ｓ体のピーク面積百分率
結果を表１に示す。

Q _R : Peak area percentage of R-form Q _S : Peak area percentage of S-form The results are shown in Table 1.

表中の数値について、粗収率（％）は粗収量より算出した。その他の項目はＨＰＬＣ面積百分率（％）を示す。なお、トルエンの沸点は約１１０．６℃である。

For the numerical values in the table, the crude yield (%) was calculated from the crude yield. Other items indicate HPLC area percentage (%). The boiling point of toluene is about 110.6 ° C.

  As shown in Table 1, in the production method of the present invention, optical isomers were hardly generated, and generation of decomposition products could be suppressed as compared with the reference example. Furthermore, disappearance of the raw material was confirmed in only 2 hours.

(Examples 2 to 4)
The same operation as in Example 1 was carried out except that the reaction temperature was changed, and duloxetine ethyl carbamate (Ib) (optical isomer: 1.56%) was used to maintain the reaction temperature at the temperature described in Table 1. The reaction temperature was examined. In each Example, the results of analyzing the reaction mixture by HPLC at 5 hours after the start of the reaction (Examples 2 and 3) or when the conversion rate reached 99% or more (Example 4) are shown in Table 2. To do.

  From the results shown in Table 2, it was found that the reaction proceeded more rapidly by raising the reaction temperature to some extent, and the production of optical isomers was also slight.

  (Example 5) Production of duloxetine hydrochloride (III)

実施例１で得られたデュロキセチン塩基（ＩＩａ）（３２．３ｇ）のメチルエチルケトン（２５７ｍＬ）、メタノール（１３ｍＬ）およびにトルエン（３２ｍＬ）からなる混合溶液に、ＨＣｌ酢酸エチル溶液（１Ｍ、１７ｍＬ）を室温にて加えた。種晶（３．１５ｍｇ、０．０５％）を加え、同温にて２時間攪拌した。その後、ゆっくり０℃まで冷却し、２時間攪拌した。析出した結晶を濾取し、メチルエチルケトン（３２ｍＬ）で４回洗浄した。５０℃で減圧乾燥を行い、表題の化合物を２７．９ｇ（収率８４％；ＨＰＬＣにおけるピークエリア：９９．９７％、光学異性体０．０２４％（反応前：０．７１１％）で得た。

To a mixed solution of duloxetine base (IIa) (32.3 g) obtained in Example 1 in methyl ethyl ketone (257 mL), methanol (13 mL), and toluene (32 mL) was added HCl ethyl acetate solution (1 M, 17 mL) at room temperature. Added at. Seed crystals (3.15 mg, 0.05%) were added, and the mixture was stirred at the same temperature for 2 hours. Then, it cooled slowly to 0 degreeC and stirred for 2 hours. The precipitated crystals were collected by filtration and washed 4 times with methyl ethyl ketone (32 mL). After drying under reduced pressure at 50 ° C., 27.9 g (yield 84%; peak area in HPLC: 99.97%, optical isomer 0.024% (before reaction: 0.711%)) was obtained. .

  This example showed that according to the present invention, high yield and high purity duloxetine hydrochloride can be obtained.

Claims (7)

The following formula (II)

A process for producing duloxetine base represented by:
Formula (I)

(Wherein R represents a C1-C4 alkyl group)
A step of mixing duloxetine alkyl carbamate represented by the formula: potassium hydroxide and toluene in the presence of a lower alcohol; and a step of heating and reacting the resulting mixture to distill off part of the solvent during the reaction. A method for producing duloxetine base.   The method for producing duloxetine base according to claim 1, wherein the potassium hydroxide is dissolved in the lower alcohol and then mixed with a toluene solution in which the duloxetine alkyl carbamate is dissolved.   The production method according to claim 1 or 2, wherein in the formula (I), R is ethyl.   The manufacturing method in any one of Claims 1-3 whose said lower alcohol is ethanol.   The manufacturing method in any one of Claims 1-4 whose said reaction temperature is 95 to 100 degree | times. To obtain a de Yurokisechin base by the method according to claims 1-5, then includes converting the duloxetine base obtained duloxetine hydrochloride, method for producing duloxetine hydrochloride.   The production method according to claim 6, wherein the mixture is converted to the duloxetine hydrochloride using a mixed solvent containing methyl ethyl ketone and methanol.