Process for the racemization of benzofuroquinolizines

Abstract

The disclosure relates to a process for the recycling of benzofuroquinolizinone, an important intermediate in the existing total synthesis of vatinoxan, and more particularly to a racemization method for benzofuroquinolizines. The disclosure also relates to the use of the product in the synthesis of vatinoxan.

Description

[0001] PROCESS FOR THE RACEMIZATION OF BENZOFUROQUINOLIZINES

[0002] FIELD OF THE DISCLOSURE

[0003] The present disclosure relates to an improved process for the manufacture of spirocyclic substituted benzofuroquinolizines, and particularly to a process for racemization and recycling of benzofuroquinolizinone (12bR)-1 ,3,4,6,7,12b-hexahydro-2H-benzo[b]furo[2,3- a]quinolizin-2-one, to obtain (12bS)-1 ,3,4,6,7,12b-hexahydro-2H-benzo[b]furo[2,3- a]quinolizin-2-one.

[0004] BACKGROUND OF THE DISCLOSURE

[0005] The compound (12bS)-1 ,3,4,6,7,12b-hexahydro-2H-benzo[b]furo[2,3-a]quinolizin-2-one is an intermediate in the process for the manufacture of the compound A / -(2-((2R,12bS)-2’- oxo-1 ,3,4,6,7,12b-hexahydrospiro[benzofuro-[2,3-a]quinolizine-2,4’-imidazolidine]-3’- yl)ethyl)-methanosulfonamide, also known as vatinoxan or MK-467 that is an important veterinary active pharmaceutical. Several processes have been proposed in the art for the manufacture of vatinoxan, for example in documents US 9,409,919 B2, EP 0259092 and US 4,942,235.

[0006] Common for all the above disclosed methods is that the enantiomerically pure intermediate (12bS)-1 ,3,4,6,7,12b-hexahydro-2H-benzo[b]furo[2,3-a]quinolizin-2-one is obtained from the corresponding racemic mixture using for example acylated L-tartaric acid, such as di- para-toluoyl-L-tartaric acid.

[0007] A problem with the current state of the art is that the R-enantiomer (12bR)-1 ,3,4,6,7,12b- hexahydro-2H-benzo[b]furo[2,3-a]quinolizin-2-one is lost in the waste stream. This is not tolerable in regard to loss of atom mass and economical and ecological perspectives.

[0008] There is a need for a process for utilizing both enantiomers of the racemic mixture, which would make the recycling of the waste stream possible. However, no general approaches to racemization exist and no racemization methods for spirocyclic benzofuroquinolizines are reported in the literature.

[0009] BRIEF DESCRIPTION OF THE DISCLOSURE

[0010] An object of the present disclosure is to provide a method to overcome the above problems.

[0011] The object of the disclosure is achieved by a method which is characterized by what is stated in the independent claims. The preferred embodiments of the disclosure are disclosed in the dependent claims. The present disclosure relates to a process for racemization of (12b / ?)- 1 ,3, 4, 6, 7,12b- hexahydro-2H-benzo[b]furo[2,3-a]quinolizin-2-one, characterized in that it comprises the steps of: a) obtaining (12b / ?)-1 ,3,4,6,7,12b-hexahydro-2H-benzo[b]furo[2,3-a]quinolizin-2-one as chiral salt derivative from the racemic mixture of (12b / ?S)-1 ,3,4,6,7,12b-hexahydro-2H- benzo[b]furo[2,3-a]quinolizin-2-one by treating (12b / ?S)-1 ,3,4,6,7,12b-hexahydro-2H- benzo[b]furo[2,3-a]quinolizin-2-one with a chiral resolving agent in an organic solvent, b) washing the (12b / ?)-1 ,3,4,6,7,12b-hexahydro-2H-benzo[b]furo[2,3-a]quinolizin-2-one salt derivative with an aqueous base to release (12b / ?)-1 ,3,4,6,7,12b-hexahydro-2H- benzo[b]furo[2,3-a]quinolizin-2-one salt derivative from the salt, c) precipitating (12b / ?)-1 ,3,4,6,7,12b-hexahydro-2H-benzo[b]furo[2,3-a]quinolizin-2-one from the organic solvent with an inorganic acid and isolating the obtained precipitate, d) slurrying the precipitated product obtained in step c) with water and heating or refluxing until it racemizes into (12b / ?S)-1 ,3,4,6,7,12b-hexahydro-2H-benzo[b]furo[2,3-a]quinolizin- 2-one salt derivative, e) adding the slurry obtained in step d) to a suitable organic solvent and adjusting pH with base to remove salt into an aqueous phase and release (12b / ?S)-1 ,3, 4, 6, 7, 12b- hexahydro-2H-benzo[b]furo[2,3-a]quinolizin-2-one into an organic phase, f) separating the organic and aqueous phases and treating the organic phase with the chiral resolving agent to gain (12bS)-1 ,3,4,6,7,12b-hexahydro-2H-benzo[b]furo[2,3- a]quinolizin-2-one as a salt derivative.

[0012] The present disclosure also relates to a product obtainable by the process of the present disclosure.

[0013] The present disclosure also relates to use of the product obtainable by the present process in the synthesis of vatinoxan.

[0014] The disclosure is based on the idea that recycling the waste stream of an already existing process, by racemization of the undesired R-enantiomer, creates more valuable process as less waste is generated and more of the desired S-enantiomer can be obtained. This leads to better overall yield in the total synthesis of vatinoxan.

[0015] Another advantage of the method of the disclosure is that it uses ecological solvents and reagents which are suitable for a large industrial scale in economical way. DEFINITIONS

[0016] The expression “a chiral resolving agent” refers to a derivatization reagent that is a chiral auxiliary used to convert a mixture of enantiomers into diastereomers, which typically involves salt formation.

[0017] The expression “a chiral salt derivative” refers to the product obtained by reacting enantiomers with a chiral resolving agent, wherein the chiral salt derivatives can be separated by conventional crystallization.

[0018] The term “HPLC” refers to high performance liquid chromatography that is a qualitative and quantitative analytical method used for separation of compounds in a mixture and typically used for determination of enantiomeric excess.

[0019] BRIEF DESCRIPTION OF THE DRAWINGS

[0020] In the following the disclosure will be described in greater detail by means of preferred embodiments with reference to the accompanying drawings, in which

[0021] Figure 1 shows (12bS)-1 ,3,4,6,7,12b-hexahydro-2H-benzo[b]furo[2,3-a]quinolizin-2-one (Compound I), the intermediate in the vatinoxan synthesis;

[0022] Figure 2 shows an embodiment of the present process in which racemic (12bRS)- 1 ,3,4,6,7,12b-hexahydro-2H-benzo[b]furo[2,3-a]quinolizin-2-one (Compound II) is treated with di-para-toluoyl-L-tartaric acid in ethyl acetate to separate (12bS)-1 ,3,4,6,7,12b- hexahydro-2H-benzo[b]furo[2,3-a]quinolizin-2-one and (12bR)-1 ,3,4,6,7,12b-hexahydro- 2H-benzo[b]furo[2,3-a]quinolizin-2-one as their tartaric acid derivatives (Compound III and Compound IV, respectively);

[0023] Figure 3 shows the racemization step in which (12bR)-1 ,3,4,6,7,12b-hexahydro-2H- benzo[b]furo[2,3-a]quinolizin-2-one hydrochloride salt (Compound V) is slurried with water and refluxed until it racemizes into (12bRS)-1 ,3,4,6,7,12b-hexahydro-2H-benzo[b]furo[2,3- a]quinolizin-2-one hydrochloric salt (Compound VI), and treating Compound VI with sodium hydroxide to obtain free racemic (12bRS)-1 ,3,4,6,7,12b-hexahydro-2H- benzo[b]furo[2,3-a]quinolizin-2-one (Compound II);

[0024] Figure 4 shows a typical HPLC chromatogram of the racemic (12bRS)-1 ,3,4,6,7,12b- hexahydro-2H-benzo[b]furo[2,3-a]quinolizin-2-one;

[0025] Figure 5 shows a typical HPLC chromatogram of the (12bR)-1 ,3,4,6,7,12b-hexahydro-2H- benzo[b]furo[2,3-a]quinolizin-2-one; and Figure 6 shows a typical HPLC chromatogram of the (12bS)-1 ,3,4,6,7,12b-hexahydro-2H- benzo[b]furo[2,3-a]quinolizin-2-one.

[0026] DETAILED DESCRIPTION OF THE DISCLOSURE

[0027] Racemization is a process in which one pure form of an enantiomer is converted into a mixture that contains equal amounts of both enantiomers, wherein the resulting mixture is said to be racemic. There are no generic approaches for racemization. It can occur under various chemical and biochemical conditions depending on the structure and chemistry of the compound in question. It may occur rapidly and spontaneously in ambient conditions, under specific basic or acidic conditions, or it may require harsh or more complex conditions.

[0028] In general, converting a tertiary carbon stereocenter into the other isomer, is challenging. Typically, the structure would need to be functionalized and / or a catalyst is needed for the change to occur.

[0029] No efficient racemization methods for spirocyclic benzofuroquinolizines have been previously known. Therefore, it was surprisingly found by the present inventors that the (12bR)-1 ,3,4,6,7,12b-hexahydro-2H-benzo[b]furo[2,3-a]quinolizin-2-one can be racemized, first converting the (12bR)-1 ,3,4,6,7,12b-hexahydro-2H-benzo[b]furo[2,3- a]quinolizin-2-one to its salt, then slurrying the (12bR)-1 ,3,4,6,7,12b-hexahydro-2H- benzo[b]furo[2,3-a]quinolizin-2-one salt with water, after which the mixture is heated to reflux. Prior to finding out successful conditions, the present inventors tested acidic and basic conditions as well as redox and photo-chemical racemization methods, which were either ineffective or led to degradation of the product. Considering the efforts, it was surprising that racemization finally happened in relatively mild conditions using only water and heat, as long as the compound was in its salt form. It was observed that in water racemization occurred when the slurry was heated above ambient temperature. Ambient temperature refers to the temperature of the surrounding environment where an experiment or process is conducted. It is typically the room temperature or the natural temperature of the environment without any artificial heating or cooling applied, which is typically around 20-25 °C. The reaction mixture can optionally be heated also to reflux. Refluxing is also a safe option, since decomposition of the product does not occur even at reflux temperatures. The refluxing can be safely continued for at least 24 hours without any decomposition of the product.

[0030] The disclosure relates to a process for racemization of (12bR)-1 ,3,4,6,7,12b-hexahydro- 2H-benzo[b]furo[2,3-a]quinolizin-2-one, characterized in that it comprises the steps of: a) obtaining (12b / ?)-1 ,3,4,6,7,12b-hexahydro-2H-benzo[b]furo[2,3-a]quinolizin-2-one as chiral salt derivative from the racemic mixture of (12b / ?S)-1 ,3,4,6,7,12b-hexahydro-2H- benzo[b]furo[2,3-a]quinolizin-2-one by treating the (12b / ?S)-1 ,3,4,6,7,12b-hexahydro-2H- benzo[b]furo[2,3-a]quinolizin-2-one with a chiral resolving agent in organic solvent using conventional methods known as such, b) washing the (12b / ?)-1 ,3,4,6,7,12b-hexahydro-2H-benzo[b]furo[2,3-a]quinolizin-2-one salt derivative with aqueous base to release the (12b / ?)-1 ,3,4,6,7,12b-hexahydro-2H- benzo[b]furo[2,3-a]quinolizin-2-one from the salt using conventional methods known as such, c) precipitating (12b / ?)-1 ,3,4,6,7,12b-hexahydro-2H-benzo[b]furo[2,3-a]quinolizin-2-one from the organic solvent with inorganic acid and isolating the obtained precipitate, d) slurrying the precipitated compound obtained in step c) with water and heating or refluxing until it racemizes into (12b / ?S)-1 ,3,4,6,7,12b-hexahydro-2H-benzo[b]furo[2,3- a]quinolizin-2-one salt derivative, e) adding the slurry to a suitable organic solvent and adjusting pH with base to remove salt into aqueous phase and release (12b / ?S)-1 ,3,4,6,7,12b-hexahydro-2H- benzo[b]furo[2,3-a]quinolizin-2-one into organic phase, f) separating the organic and aqueous phases and treating the organic phase with chiral resolving agent to gain desired (12bS)-1 ,3,4,6,7,12b-hexahydro-2H-benzo[b]furo[2,3- a]quinolizin-2-one as a salt derivative.

[0031] According to an embodiment of the disclosure in steps a) and f) the chiral resolving agent is selected from the group consisting of L-tartaric acid, acylated L-tartaric acid, O,O'-di- para-toluoyl-L-tartaric acid, and dibenzoyl-L-tartaric acid.

[0032] According to a further embodiment of the disclosure, the chiral resolving agent in steps a) and f) is O,O’-di-para-toluoyl L-tartaric acid.

[0033] According to an embodiment of the disclosure, in steps a) and e) the organic solvent is selected from the group consisting of toluene, 2-butanone, isopropyl acetate, ethyl acetate, dichloromethane, methyl tert-butyl ether (MTBE), heptane, hexane, tetra hydrofuran (THF), and mixtures thereof.

[0034] According to an embodiment of the disclosure, in steps b) and f) the aqueous base is selected from the group consisting of sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, and mixtures thereof. According to an embodiment of the disclosure, in step c) the inorganic acid is selected from the group consisting of hydrobromide, methanesulfonate, nitrate, sulfate, phosphate, hydrochloric acid, and mixtures thereof.

[0035] In a further embodiment of the disclosure, in step c) the inorganic acid is hydrochloric acid.

[0036] According to an embodiment of the disclosure, the solvent in step d) is preferably water. However, a skilled person in the art knows that a solvent can be changed into another similar solvent without the solvent change affecting the reaction. Water is a polar, protic solvent, and examples of other similar polar, protic solvents are acetic acid, formic acid, propionic acid and butyric acid. It is common knowledge in the art that DMSO can sometimes be used instead of water as well. Any solvent similar to listed above can be used in this disclosure. A skilled person can choose a suitable solvent according to preference.

[0037] In an embodiment step d) is carried out by slurrying the precipitated product obtained in step c) with water and heating until it racemizes into (12bRS)-1 ,3,4,6,7,12b-hexahydro- 2H-benzo[b]furo[2,3-a]quinolizin-2-one salt derivative.

[0038] In another embodiment step d) is carried out by slurrying the precipitated product obtained in step c) with water and refluxing until it racemizes into (12bRS)-1 ,3,4,6,7,12b-hexahydro- 2H-benzo[b]furo[2,3-a]quinolizin-2-one salt derivative.

[0039] A skilled person can adjust the heating temperature accordingly based on the chosen solvent.

[0040] In an embodiment, the slurry is heated for 5 - 30 hours, preferably for 9 - 24 hours. In an embodiment the slurry is heated for at least 9 hours. In another embodiment the slurry is heated for about 24 hours

[0041] In an embodiment, the slurry is refluxed. The slurry is refluxed for 5 - 30 hours, preferably for 9 - 24 hours. In an embodiment the slurry is refluxed for at least 9 hours. In another embodiment the slurry is refluxed for about 24 hours.

[0042] The disclosure also relates to a product obtainable by any one of the embodiments.

[0043] The disclosure also relates to the use of the product according to the embodiments of the disclosure in the synthesis of vatinoxan.

[0044] Steps a) and b) describe the process for the recovery of (12bR)-1 , 3, 4, 6,7,12b-hexahydro- 2H-benzo[b]furo[2,3-a]quinolizin-2-one as its tartaric acid salt from the waste stream that has been obtained from the synthesis of the vatinoxan intermediate (12bS)-1 ,3,4,6,7,12b- hexahydro-2H-benzo[b]furo[2,3-a]quinolizin-2-one. Step c) describes the process in which (12bR)-1 ,3,4,6,7,12b-hexahydro-2H- benzo[b]furo[2,3-a]quinolizin-2-one is precipitated and isolated as the corresponding HCI salt. Salt formation, in which the product precipitates as the corresponding salt, and isolation are performed using conventional methods known as such. A person skilled in the art is familiar with the methods. It is essential that the compound is in a salt form for the racemization to occur in the next step.

[0045] Steps d)-f) are illustrated in Figure 3 describing the racemization reaction in step d), followed by steps e) and f) that describe the process for releasing the HCI salt from the racemate, after which the (12bS)-1 ,3,4,6,7,12b-hexahydro-2H-benzo[b]furo[2,3- a]quinolizin-2-one is recovered as the corresponding tartaric acid salt that can be used further. Heating and refluxing are performed using conventional methods known as such. Releasing a product from its corresponding salt is a performed using conventional methods known as such. A skilled person is familiar with the methods and can choose suitable conditions.

[0046] Full racemization in step d) is typically obtained after heating or refluxing the reaction mixture for at least 9 hours. Heating or refluxing can typically be continued for at least 24 hours without significant decomposition of the compound.

[0047] According to a preferred embodiment of the disclosure, the disclosure relates to a process for racemization of (12bR)-1 ,3,4,6,7,12b-hexahydro-2H-benzo[b]furo[2,3-a]quinolizin-2- one, characterized in that it comprises the steps of: a) obtaining (12bR)-1 ,3,4,6,7,12b-hexahydro-2H-benzo[b]furo[2,3-a]quinolizin-2-one as tartaric acid salt derivative from the racemic mixture of (12bRS)-1 ,3,4,6,7,12b-hexahydro- 2H-benzo[b]furo[2,3-a]quinolizin-2-one by treating the (12bRS)-1 ,3,4,6,7,12b-hexahydro- 2H-benzo[b]furo[2,3-a]quinolizin-2-one with O,O'-di-para-toluoyl-L-tartaric acid in ethyl acetate, b) washing the (12bR)-1 ,3,4,6,7,12b-hexahydro-2H-benzo[b]furo[2,3-a]quinolizin-2-one salt derivative with sodium hydroxide to release (12bR)-1 ,3,4,6,7,12b-hexahydro-2H- benzo[b]furo[2,3-a]quinolizin-2-one from the tartaric acid salt, c) precipitating (12bR)-1 ,3,4,6,7,12b-hexahydro-2H-benzo[b]furo[2,3-a]quinolizin-2-one from ethyl acetate with hydrochloric acid and isolating the obtained precipitate, d) slurrying the isolated compound obtained in step c) with water and heating or refluxing until it racemizes into (12bRS)-1 ,3,4,6,7,12b-hexahydro-2H-benzo[b]furo[2,3-a]quinolizin- 2-one hydrochloride salt derivative, e) adding the slurry obtained in step d) to ethyl acetate and adjusting pH with sodium hydroxide to remove salt into aqueous phase and release (12b / ?S)-1 ,3, 4, 6, 7,12b- hexahydro-2H-benzo[b]furo[2,3-a]quinolizin-2-one into organic phase, f) separating the organic and aqueous phases and treating the organic phase with 0,0’- di-para-toluoyl-L-tartaric acid to gain (12bS)-1 ,3,4,6,7,12b-hexahydro-2H- benzo[b]furo[2,3-a]quinolizin-2-one as a tartaric acid salt derivative.

[0048] In one embodiment of the disclosure, an organic solution consisting mainly of ethyl acetate and (12b / ?)-1 ,3,4,6,7,12b-hexahydro-2H-benzo[b]furo[2,3-a]quinolizin-2-one DTTA salt is charged into reactor. To the mixed solution is added MQ-water and then 50% sodium hydroxide is added with mixing. Organic phase is separated and washed with MQ-water.

[0049] To the organic phase is slowly added hydrochloric acid (30%). (12b / ?)- 1 ,3, 4, 6, 7,12b- hexahydro-2H-benzo[b]furo[2,3-a]quinolizin-2-one hydrochloric salt precipitates out from the solution and is isolated by filtration and used in the next step.

[0050] Then (12b / ?)-1 ,3,4,6,7,12b-hexahydro-2H-benzo[b]furo[2,3-a]quinolizin-2-one hydrochloride salt is charged in the reactor with a condenser. MQ-water is added into the reactor. The suspension is heated until water starts to reflux. Suspension is refluxed, after which is cooled to about 60 °C. To the suspension is charged sodium carbonate, ethyl acetate and the suspension is mixed. The pH is adjusted to over 10 with additional sodium carbonate. The suspension is cooled to 20-25 °C and the organic phase is separated and washed with MQ-water.

[0051] The water content of the organic phase is adjusted to 1.8 weight-% and the mixture is mixed at 20-25 °C. To the organic phase is added O,O’-di-p-toluyl-l-tartaric acid.

[0052] The crystallization mixture is then mixed at 20-25 °C for 18 hours and then filtered to isolate (12bS)-1 ,3,4,6,7,12b-hexahydro-2H-benzo[b]furo[2,3-a]quinolizin-2-one DTTA salt enriched crystals. The mother liquor of crystallization is then collected for further recycling.

[0053] The isolated DTTA salt of (12bS)-1 ,3,4,6,7,12b-hexahydro-2H-benzo[b]furo[2,3- a]quinolizin-2-one is then dissolved in ethyl acetate and sodium carbonate is added with MQ-water. The solution is heated to 50 °C and mixed.

[0054] After cooling the solution to 20-25°C, the organic phase is separated and washed with MQ- water. Organic phase is then evaporated to dryness and isopropanol is added, mixture is heated to reflux and then cooled to 20-25 °C. The (12bS)-1 ,3,4,6,7,12b-hexahydro-2H- benzo[b]furo[2,3-a]quinolizin-2-one is isolated from crystallization mixture and dried in vacuum oven. According to another preferred embodiment of the disclosure, the product obtainable by any one of the embodiments is used in the synthesis of vatinoxan.

[0055] EXAMPLES

[0056] Example 1 : Process for the recovery of (12b / ?)-1 ,3,4,6,7,12b-hexahydro-2H- benzo[b1furo[2,3-a1quinolizin-2-one hydrochloride salt from the waste stream.

[0057] The organic solution (5.5 liter) consisting mainly of ethyl acetate and (12b / ?)- 1 ,3, 4, 6, 7,12b- hexahydro-2H-benzo[b]furo[2,3-a]quinolizin-2-one DTTA salt was charged into reactor. To the mixed solution was added 2 liters of MQ-water and then 50% sodium hydroxide (52 g) was added with mixing. Organic phase was separated after 15 minutes and washed with 1 liter of MQ-water.

[0058] To the organic phase was slowly added hydrochloric acid (30%, 50 g), and (12b / ?)- 1 ,3,4,6,7,12b-hexahydro-2H-benzo[b]furo[2,3-a]quinolizin-2-one hydrochloric salt precipitated out from the solution and was isolated by filtration and used in the next step. HPLC 95.2%, yield 95 % from available R-enantiomer (Figure 5).

[0059] Example 2: Racemization of (12b / ?)-1 ,3,4,6,7,12b-hexahydro-2H-benzo[b1furo[2,3- alquinolizin-2-one hydrochloric salt, and isolation of (12bS)-1 ,3,4,6,7,12b-hexahydro-2H- benzo[b1furo[2,3-a1quinolizin-2-one O,O’-di-para-toluoyl-L-tartaric acid (DTTA) salt

[0060] 300 g (1.08 mol) of (12b / ?)-1 ,3,4,6,7,12b-hexahydro-2H-benzo[b]furo[2,3-a]quinolizin-2- one hydrochloride salt was charged in reactor with condenser. 3000 ml of MQ-water was added into the reactor. The suspension was heated until water started to reflux. Suspension was refluxed for 24 hours, after which it was cooled to 60 °C. To the suspension was charged sodium carbonate (0.85 mol), 2700 ml of ethyl acetate and the suspension was mixed for 15 minutes. The pH was adjusted to over 10 with additional sodium carbonate (0.2 mol). The suspension was cooled to 25 °C and the organic phase was separated and washed with 600 ml of MQ-water. Organic phase was analyzed and verified for the racemization (HPLC: 50.3:49.7, Figure 4).

[0061] The water content of the organic phase was adjusted to 1 .8 weight-% and the mixture was mixed at 21 °C for 15 minutes. To the organic phase was added O,O’-di-p-toluyl-L-tartaric acid in four parts (1 .0 mol).

[0062] The crystallization mixture was then mixed at 20-25 °C for 18 hours and then filtered to isolate (12bS)-1 ,3,4,6,7,12b-hexahydro-2H-benzo[b]furo[2,3-a]quinolizin-2-one DTTA salt enriched crystals (HPLC 90.4 % S-form). The mother liquor of crystallization was then collected for further recycling.

[0063] Example 3: Isolation of (12bS)-1 ,3,4,6,7,12b-hexahvdro-2H-benzo[b1furo[2,3-a1quinolizin- 2-one The isolated DTTA salt of (12bS)-1 ,3,4,6,7,12b-hexahydro-2H-benzo[b]furo[2,3- a]quinolizin-2-one was then dissolved in ethyl acetate (3400 ml) and sodium carbonate was added (2 mol) with 2000 ml MQ-water. The solution was heated to 50 °C and mixed for 15 minutes.

[0064] After cooling the solution to 25°C, the organic phase was separated and washed with 1000 ml MQ-water. Organic phase was then evaporated to dryness and 600 ml of isopropanol was added, mixture was heated to reflux and then cooled to 22 °C. The (12bS)- 1 ,3,4,6,7,12b-hexahydro-2H-benzo[b]furo[2,3-a]quinolizin-2-one was isolated from crystallization mixture and dried in vacuum oven. The isolated yield was 73 grams (56 % from available S-enantiomer) and HPLC purity 99.5 % (Figure 6).

Claims

CLAIMS1. A process for racemization of (12b / ?)-1 ,3,4,6,7,12b-hexahydro-2H-benzo[b]furo[2,3- a]quinolizin-2-one, characterized in that it comprises the steps of: a) obtaining (12b / ?)-1 ,3,4,6,7,12b-hexahydro-2H-benzo[b]furo[2,3-a]quinolizin-2-one as chiral salt derivative from the racemic mixture of (12b / ?S)-1 ,3,4,6,7,12b-hexahydro-2H- benzo[b]furo[2,3-a]quinolizin-2-one by treating (12b / ?S)-1 ,3,4,6,7,12b-hexahydro-2H- benzo[b]furo[2,3-a]quinolizin-2-one with a chiral resolving agent in an organic solvent, b) washing the (12b / ?)-1 ,3,4,6,7,12b-hexahydro-2H-benzo[b]furo[2,3-a]quinolizin-2-one salt derivative with an aqueous base to release (12b / ?)-1 ,3,4,6,7,12b-hexahydro-2H- benzo[b]furo[2,3-a]quinolizin-2-one salt derivative from the salt, c) precipitating (12b / ?)-1 ,3,4,6,7,12b-hexahydro-2H-benzo[b]furo[2,3-a]quinolizin-2-one from the organic solvent with an inorganic acid and isolating the obtained precipitate, d) slurrying the precipitated product obtained in step c) with water and heating or refluxing until it racemizes into (12b / ?S)-1 ,3,4,6,7,12b-hexahydro-2H-benzo[b]furo[2,3-a]quinolizin- 2-one salt derivative, e) adding the slurry obtained in step d) to a suitable organic solvent and adjusting pH with base to remove salt into an aqueous phase and release (12b / ?S)-1 ,3, 4, 6, 7, 12b- hexahydro-2H-benzo[b]furo[2,3-a]quinolizin-2-one into an organic phase, f) separating the organic and aqueous phases and treating the organic phase with the chiral resolving agent to gain (12bS)-1 ,3,4,6,7,12b-hexahydro-2H-benzo[b]furo[2,3- a]quinolizin-2-one as a salt derivative.

2. The process according to claim 1 , characterized in that in steps a) and f) the chiral resolving agent is selected from the group consisting of L-tartaric acid, acylated L-tartaric acid, O,O'-di-para-toluoyl-L-tartaric acid, and dibenzoyl-L-tartaric acid.

3. The process according to any one of the preceding claims, characterized in that the chiral resolving agent in steps a) and f) is O,O’-di-para-toluoyl L-tartaric acid.

4. The process according to any one of the preceding claims, characterized in that in steps a) and e) the organic solvent is selected from the group consisting of toluene, 2- butanone, isopropyl acetate, ethyl acetate, dichloromethane, methyl tert-butyl ether, heptane, hexane, tetrahydrofuran, and mixtures thereof.

5. The process according to any one of the preceding claims, characterized in that in steps b) and f) the aqueous base is selected from the group consisting of sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, and mixtures thereof.

6. The process according to any one of the preceding claims, characterized in that in step c) the inorganic acid is selected from the group consisting of hydrobromide, methanesulfonate, nitrate, sulfate, phosphate, hydrochloric acid, and mixtures thereof.

7. The process according to any one of the preceding claims, characterized in that in step c) the inorganic acid is hydrochloric acid.

8. The process according to any one of the preceding claims, characterized in that in step d) the slurry is refluxed for 5-30 hours, preferably for 9-24 hours.

9. A product obtainable by the process of any one of claims 1 to 8.

10. Use of the product according to claim 9 in the synthesis of vatinoxan.

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