Industrial process for the preparation of (5S, 10S)-10-benzyl-16-methyl-11, 14, 18-trioxo-15, 17, 19-trioxa-2,7,8-trithia-12-azahenicosan-5-aminium(E)-3-carboxyacrylate salt

Abstract

The present invention relates to an industrial process for the preparation of (5S,10S)-10-benzyl-16-methyl-11,14,18-trioxo-15,17,19-trioxa-2,7,8-trithia-12-azahenicosan-5-aminium (E)-3-carboxyacrylate salt of following formula (I): wherein X is fumarate. This process comprises the following successive key steps: a kinetic resolution, formation of disulfide compound, peptide coupling, and anion exchange reaction to obtain the desired product of formula (I). ##STR00001##

Claims

1. An industrial process for the preparation of (5S,10S)-10-benzyl-16-methyl-11,14,18-trioxo-15,17,19-trioxa-2,7,8-trithia-12-azahenicosan-5-aminium (E)-3-carboxyacrylate salt of following formula (I): ##STR00029## comprising the following successive synthetic steps performed in degassed organic polar or apolar, protic or aprotic solvents: (1) preparing compound E of following formula with an enantiomeric excess higher than 95% ##STR00030## by 1a) reacting A of following formula ##STR00031## with 0.5-0.6 molar equivalents of quinine in organic polar and aprotic solvents; 1b) crystallizing the resulting quinine salt at temperature ranging from 10 C. to 20 C., in same organic solvent than the one used in step 1a, wherein crystallization is initiated by adding few crystals of the desired enantiomer salt to initiate the crystallization, then; 1c) recrystallizing the salt obtained after step 1b at the same temperature range and same solvent than the one used in step 1b; 1d) Recovering of compound E by: 1d.1) recovering compound (D) of following formula ##STR00032## 1d.2) deprotecting thiolacetate in polar and protic solvent such as MeOH; 1e) recovering of quinine; (2) preparing compound F of following formula ##STR00033## By 2a) reacting first 1.1 molar equivalents of said compound E with 1 molar equivalent of chlorocarbonyl sulfenyl chloride, in polar and aprotic solvent, then; 2b) reacting the intermediate obtained after step 2a with 0.9 molar equivalents of compound B of following formula ##STR00034## in solution with 1 molar equivalent of Et.sub.3N in same solvent than the one used in step 2a; (3) preparing compound G of following formula ##STR00035## by reacting said compound F with amino-ester C of following formula, wherein Y.sup.is an anion: ##STR00036## in polar solvent; (4) then, recovering salt (I) of followed formula ##STR00037## by 4a) adding 5 molar equivalent of formic acid to said compound G; 4b) exchanging the form ate by a fumarate using a continuous flow technology.

2. The industrial process according to claim 1, wherein crystallization in step 1b comprises the following successive steps: 1b.1) dissolution of quinine salt at solubilizing temperature, then; 1b.2) cooling the mixture obtained in step 1b.1, until temperature ranging from 10 C. to 20 C.; 1b.3) isolating quinine salt obtained after step 1b.2 by filtration.

3. The industrial process, according to claim 1, wherein in step 1a solvent is ethyl acetate.

4. The industrial process, according to claim 1, wherein step 1d.1 further comprises the following successive steps: 1d.1.1) suspension of quinine salt obtained in step 1c.3 or 1c.4 in HCl in solution in water, then; 1d.1.2) extraction of compound (D) of following formula ##STR00038## with an aprotic and polar solvent, in particular with ethyl acetate, then; 1d.1.3) concentration in vacuum to obtain an oil.

5. The industrial process, according to claim 1, further comprising after step 1d.1, the following successive steps: 1d.2.1) alkaline hydrolysis in polar and protic solvent, then 1d.2.2) acidic treatment, then; 1d.2.3) extraction of compound (E) with organic solvent.

6. The industrial process according to claim 1, wherein the recovering of quinine in step le comprises the following successive steps: 1e.1) combining the aqueous phases obtained in step 1d.2.1 and in step 1d.2.2, then; 1e.2) adding 20% by weight of aqueous solution of NaOH in water to adjust the pH to 12, then; 1e.3) extracting the resulting mixture obtained in step 1e.2 with AcOEt, then; 1e.4) concentrating under vacuum the resulting organic layer obtained in step 1e.3, then; 1e.5) adding petroleum ether at temperature ranging from 10 C. to 20 C., then; 1e.6) filtrating the resulting solid obtained at the end of step 1e.5 and recovering quinine.

7. The industrial process according to claim 1, further comprising after step 2b and before step 3 the following successive steps: 2b.1) adding water comprising 10% in weight of citric acid to the reaction mixture obtained after step 2b, until pH<7, then; 2b.2) extracting compound F with AcOEt.

8. The industrial process according to claim 7, wherein after step 2b.2 compound F is precipitated in Hexane.

9. The industrial process, according to claim 1, wherein step 3 comprises the following steps: 3a) solubilizing compound F in polar and aprotic solvent, then 3b) to the reaction mixture obtained after step 3a adding1.2 molar equivalents of O -Benzotriazol-1-yl-N,N,N,N-tetramethyluronium hexafluorophosphate and diisopropyl-ethyl-amine. 3c) to the reaction mixture obtained after step 3b adding 1.3 molar equivalents of aminoester C.

10. The industrial process according to claim 1, wherein step 3 is performed at a temperature comprised between 2 C. and 10 C.

11. The industrial process according to claim 9, wherein in step 3a, the compound (F) is put in organic solvent at a concentration of 0.05 M-0.3 M.

12. The industrial process, according to claim 9, wherein after step 3c compound G is obtained by following successive steps: 3c.1) recovering organic layer containing compound G; 3c.2) precipitating compound G present in organic layer of step 3c.1 by adding a mixture of petroleum ether (hexane)/AcOEt in 8/1-6/1 volume proportion.

13. The industrial process, according to claim 12, wherein step 3c.1 comprises the following successive steps: 3c.1.1) adding water to the resulting mixture obtained in step 3c, then; 3c.1.2) without concentrating the reaction solvent, extracting the product obtained after step 3c.1.1 with polar aprotic solvent.

14. The industrial process according claim 1, wherein compound C is prepared by a process comprising the following successive synthetic steps: ) reacting 1.1 molar equivalents of Boc-glycine with 1.2 molar equivalent of Et.sub.3N in ethyl acetate, then; ) reacting product obtained in step with 1 molar equivalents of ethyl-1-chloroethylcarbonate, and 0.2 molar equivalents of potassium iodide. ) reacting product obtained in step with 2 molar equivalents of HCl gas in ethyl acetate at temperature ranging from 5 C. to 10 C., and recovering C.

15. The industrial process according to claim 1, wherein after adding formic acid in step 4a, the process further comprises the following successive steps: 4a.1) co-evaporating product obtained after adding formic acid with toluene giving compound (H), the formate salt of (G), and organic layer with toluene, then; 4a.2) to the compound (H) obtained after step 4a, adding ethyl acetate, and then washing the resulting mixture with brine at a temperature ranging from 0 C. to 10 C.

16. The industrial process, according to claim 1, wherein anion exchange is performed by the following steps: 4b.1) adding a solution of 2% NaOH by weight in water to a product obtained after step 4a.2 at temperature ranging from 0 C. to 10 C., then; 4d) adding a solution 5% fumaric acid by weight in EtOH to the mixture obtained after step 4b.1 to isolated crystallized compound (I) using flow continuous process.

17. The industrial process, according to claim 2, wherein the cooling in step 1b.2) is performed at a rate of 3-10 C./h.

18. The industrial process, according to claim 8, wherein after precipitation in Hexane compound F is recrystallized from Hexane/AcOEt, in 5.5/1-7.5/1 in a volume proportion.

19. The industrial process, according to claim 13, wherein in step 3c.1.2) the polar aprotic solvent is AcOEt.

Description

DESCRIPTION OF FIGURES

(1) FIG. 1 describes the block diagram of step 4b exposing the continuous flow process.

(2) For the realization of step 4b, the solution of 3.3% by weight of compound (H) in AcOEt was introduced via 1. Consecutively, the solution of 2% NaOH by weight in water was added via 2.

(3) Step 4b.1: the mixture reacted continuously at 5 C. and at pH ranging from 8-9, allowing a conversion of the formate salt (H) into the free base compound (I).

(4) In section 3, we obtained a biphasic mixture, which was then extracted continuously, at 5 C. in 4. Water phase was stored in container in 5, and the organic phase obtained in 6, was engaged in step 4b.2. A solution of 5% fumaric acid by weight in EtOH was introduced via 7, to the step 4b.2. The mixture in step 4b.2 reacted continuously at 5 C. A solution of compound (I) was obtained in 8. A continuous distillation of solvent was then performed in 9. Distilled solvent was stored in container in 10, and the compound (I) was obtained in 11.

(5) FIG. 2 describes the continuous apparatus for the preparation of compound (I).

(6) For the realization of step 4b at an industrial scale, the continuous apparatus consisting of a mixer-settler and a Continuous Stirred Tank Reactor (CSTR2) was assembled. The mixer-settler was formed by a Continuous Stirred Tank Reactor (CSTR1) and a settler 4. CSTR1 was the reactor wherein step 4b.1 was performed. CSTR2 was the reactor wherein step 4b.2 was performed.

(7) Tank 1 was charged with the solution of 3.3% by weight of compound (H) in AcOEt, and the said solution was engaged into CSTR1 reactor with a feed F1 at 1095 g/h. Consequently, Tank 2 was charged with the solution of 2% NaOH by weight in water and the said solution was then engaged in CRST1 reactor with a feed F2 at 348 g/h. The pH was controlled via 1 during all the stirring to maintain it at a range from 8 to 8.5. The biphasic reaction mixture overflew from CSTR1 into the settler where phases were separated. The aqueous phase was stored in Tank 4 with an outflow 3 of 375 g/h. The organic phase containing compound (I) free base was engaged in CSTR2 reactor with a feed F3 at 1068 g/h. Consequently, Tank 3 was charged with the solution of 5% fumaric acid by weight in EtOH and the said solution was then engaged in CRST2 reactor with a feed F4 at 142 g/h.

(8) F4 was regulated in order to have a molar ratio of 0.95 between theoretical amount of compound (I) contained in F3 and fumaric acid. The reaction mixture containing compound (I) solution overflew from CSTR2 into Tank 5 with an outflow 5 of 1201 g/h, wherein the said solution containing compound (I) was collected and stored for the length of experiment.

(9) All the equipment was thermostated at temperature of 5 C.

(10) Concentration of crude compound (I) fumarate solution resulting from the continuous process was completed by batch wise vacuum distillation, and then crystallization was achieved in Diisopropyl Ether. Compound (I) was obtained as a white solid, with an overall molar yield, from compound (F), of 84%.

(11) Isolated compound (I), obtained according to the developed method, was analyzed by HPLC, and compared with the compound (I) sample, obtained according to the previous batch procedure (WO2007/048787).

(12) Content of impurities is significantly lower in the compound (I) sample from continuous process.

(13) In an illustrative embodiment, flow continuous process was performed with 0.15 kg of compound (G) scale size.

EXAMPLES

(14) In the present invention, room temperature means a temperature ranging from 18 C. to 28 C., preferably ranging from 20 C. to 25 C.

(15) 1Studies on Quinine Quantity Useful for the Step 1.

(16) Different quinine providers are tested as resolving agent in conditions described above for the kinetic resolution in step 1 (Table 1). The obtained results showed that a slight difference in chiral purity with Vital Health Care sample.

(17) TABLE-US-00001 TABLE 1 different quinine providers tested for the kinetic resolution in step 1 Yield S/R Yield Supplier Purity (Oil) ratio ee (S) Vital Health Care 99% 35% 97.1:2.9 94.2% 68% Buchler 99.10% 35.25% 96.1:3.9 92.2% 67.75%

(18) It was hypothesised that both quinine samples had a different assay and therefore a different equivalent of pure quinine was used in both trials.

(19) Using Buchler sample, the resolution was tested with three different molar equivalents of quinine (0.5, 0.55 and 0.6) starting from racemic mixture of compound (A), and giving the compound (D) isolated as oil (Table 2).

(20) TABLE-US-00002 TABLE 2 Kinetic resolution with different molar equivalents of quinine Buchler provider. Yield S/R S/R Yield Equiv. Purity (Oil) (Solid cryst) (Oil) ee (S) 0.50 98.40% 32.1% 92.8:7.2 98.7:1.3 97.4% 63.4% 0.55 99.52% 33.7% 90.1:6.8 98.7:1.2 97.5% 66.6% 0.60 99.10% 35.25% 88.9:10.6 96.1:3.9 92.2% 67.7%

(21) These tests showed that an excess of quinine compared to the 0.5 molar equivalents of S-enantiomer led to a loss of chiral purity.

(22) In an opposite trend, lowering equivalent of quinine to 0.5 molar equivalents and using 1 molar equivalent of compound (A) led a decrease in recovering of S enantiomer (63.4% vs 66.6%) without significant chiral purity gain. These results could explain why a better chiral purity could be obtained using 0.6 molar equivalent of quinine of a lower assay (Table 2). Since quinine sample from Buchler was taken from an industrial batch in stock and given its superior quality profile, Buchler was selected as the provider.

(23) In an illustrative embodiment, 0.55 molar equivalents of quinine were preferably retained from laboratory trials as compromise for chiral purity and enantiomer recovery.

(24) The solid quinine salt was tested by thermal stress at 100 C. for 36 hours and it is assumed to be stable at this stage. Despite a change of aspect from white crystalline to semi-melted beige solid, the sample did not displayed visible degradation by HPLC.

(25) In an industrial point of view, the storing of compound (D) is made under its corresponding quinine salt, and the said quinine salt is then engaged in the following step 1d.2 wherein the solvent is switched from ethyl acetate to methanol.

(26) 2Step a: Resolution/Recrystallization

(27) A resolution on 5 kg scale is described on Table 3.

(28) TABLE-US-00003 TABLE 3 Materials used for resolution of 5 kg of compound (A) with Quinine Material M.W. Quantity Moles Eq. 2-Acetylthiomethyl- 238.3 5000 g 21 mol 1 3-phenylpropionic acid Quinine 324.4 4080 g 12.6 mol 0.6 AcOEt 170 L Conc. HCl aqueous 2 L solution (S)-2-acetylthiomethyl- 238.3 1884 g (75% mol. Yield related to 3-phenylpropionic acid (S) enantiomer, 98.95% chemical purity, 99.5% chiral purity Maximum volume: 103 L

(29) General Procedure for Industrial Kinetic Resolution:

(30) Different parameters were evaluated and a typical procedure is described below.

(31) Industrial Preferred Procedure for Crystallization: 1) Charging 90 L of AcOEt, 5.0 kg (21 mol) of compound (A) and 4.08 kg (12.6 mol) of quinine in a reactor; 2) Rinse the addition funnel with 10 L of AcOEt to flush the solid detained on the wall of the funnel into the reactor, and stir the mixture at temperature ranging from 10 C. to 15 C. for 20 min; 3) Heating the mixture to 45 C. and stirring the mixture at 45 C. till a clear solution was formed; 4) Cooling down the solution at a speed of 5 C./h to 40 C.; 5) Adding 1 g of seed which have 86% of chiral purity; 6) Cooling down the mixture at a speed of 5 C./h to temperature ranging from 10 C. to 20 C.; 7) Stirring the mixture at temperature ranging from 10 C. to 15 C. for an additional 16 h; 8) Filtering the quinine salt product after crystallization and keeping the filtrate in a container (the room temperature was 11 C. when the mixture was followed out and filtered); 9) Analyzing the filter cake with HPLC to check the chiral purity, preferably 84% of chiral purity is obtained;

(32) Industrial Preferred Procedure for Recrystallization: 10) Charging the wet cake obtained in the operation 9 in another reactor; 11) Adding 70 L of AcOEt; 12) Heating the mixture at 60 C. and under stirring till the entire solid was dissolved; 13) Cooling down the solution at a speed of 5 C./h to room temperature (when the temperature reaches 40 C., the precipitate started to be formed); 14) Stirring the mixture at temperature ranging from 10 C. to 15 C. overnight (16 h); 15) Filtering the recrystallized quinine salt (the room temperature was 11 C. when the mixture was flowed out and filtered) and keeping the filtrate in a container; 16) Analyzing the filter cake with HPLC to check the chiral purity, preferably 95.5% of chiral purity is obtained;

(33) Recovering the AcOEt Solvent Used in Preceding Process (Operations 1 to 16): 17) Charging 30 L of the filtrate obtained in the operation 15 in a reactor; 18) Adding 10 L of 0.5 M aqueous solution of NaOH in water, until pH>10, and stirring the mixture at room temperature for 20 min; 19) Separating the organic phase and storing the aqueous phase in a container; 20) Analyzing the organic phase with HPLC.

(34) If 2-acetylthiomethyl-3-phenylpropionic acid (A) cannot be detected, go to next operation. If it can be detected, wash the organic phase with water till no 2-acetylthiomethyl-3-phenylpropionic acid (A) can be detected in the organic phase;

(35) Recovering Free Compound (D): 21) Transferring the organic phase obtained in operation 19 into a reactor; 22) Adding the wet cake obtained in the operation 15; 23) Adding 10 L of water and 2 L of aqueous solution of HCl 12 N and stirring the mixture at room temperature, for an additional 30 min (pH of the aqueous phase was 1); 24) Separating the organic phase of product and keeping the aqueous phase in a container; 25) Washing the organic phase with about 5 L of water, and monitoring the washing by HPLC to detect quinine in the organic phase; 26) Concentrating the organic phase at temperature ranging from 40 C. to 45 C. and under vacuum to remove the solvent as complete as possible; 27) Adding 2.5 L of methanol into the residue and concentrating again the mixture at temperature ranging from 40 C. to 45 C. and under vacuum to chase out the remaining solvent of AcOEt; 28) Repeating the operation 27 once to give 2.1 kg of oil product of compound (D); 29) NMR analysis shows a conversion of quinine salt of (D) into free compound (D) of 89.8%. So, 1884 g of compound (D) are obtained with 75.4% yield relative to (S) enantiomer, and 98.9% chemical purity.
2.2 Step b: Recovering of Quinine at the End of Step 1.

(36) Another attractive point of chemical resolution is the recovery of the chiral agent as described below: 1) Charging the remaining filtrate (about 30 L) obtained in the operation of 15 in Step a in a reactor; 2) Adding 10 L of 0.5 M aqueous solution of NaOH in water and stirring the mixture at room temperature, for an additional 20 min (pH of the aqueous phase was about 12); 3) Separating the organic phase and storing the aqueous phase in a container; 4) Washing the organic phase with water and monitoring the washing by HPLC to detect 2-acetylthiomethyl-3-phenylpropionic acid in organic phase; 5) Keeping the organic phase in a container; 6) Charging the filtrate (about 90 L) obtained in the operation 8 in Step a in another reactor 7) Adding 6 L of concentrated aqueous solution of HCl to adjust the pH to 12 8) Separating the aqueous phase and store the organic phase in a container for recovering the AcOEt by distillation 9) Combining the aqueous phase obtained in the operations 19 and 24 in Step 1 and the aqueous phase obtained in the operations 3 and 8 in step b; 10) Adding 20% by weight of aqueous solution of NaOH in water to adjust the pH to 12; 11) Adding the AcOEt obtained in the operation 5 and stirring the mixture at room temperature for an additional 20 min; 12) Separating the organic phase and extracting the aqueous phase with 10 L of AcOEt; 13) Combining the organic solutions and concentrating it at temperature ranging from 40 C. to 45 C. and under vacuum to a volume of about 3.0 L; 14) Under vigorously stirring, adding 10 L of petroleum ether at temperature ranging from 10 C. to 20 C.; 15) Stirring the mixture at temperature ranging from 10 C. to 20 C. for an additional 1 h; 16) Filtering the mixture to isolate the solid quinine product; 17) Drying the filter cake at temperature ranging from 50 C. to 55 C. and under vacuum to give 1832 g of white solid product of quinine (80% of recovery).

(37) Using similar procedure, batch such as 150 kg of quinine salt was manufactured.

(38) 2.3 Determination of the Ee Value of Compound (D)

(39) Procedure:

(40) 1) Mixing L-Ala-OMe.HCl with 1.0 molar equivalent of compound (D) in DCM, then; 2) Stirring at temperature ranging from 10 C. to 20 C. till a solution is formed, then; 3) Adding 1.5 molar equivalents of EDCl and 2 molar equivalents of Et.sub.3N at room temperature, and stirring for an additional 1-2 min, then; 4) Removing the solvent in vacuum, then; 5) Adding AcOEt to dissolve the residue, then; 6) Washing consecutively the solution with 10% in weight of citric acid in water, then with sodium bicarbonate aqueous solution, then with water and then with brine, then; 7) Removing AcOEt and recovering a solid product. 8) Dissolving the said product obtained in operation 7 in CDCl.sub.3 for 1H NMR analysis.

(41) Methods for Calculation of the Enantiomeric Excess: 1) Integration of the peak at 6.0 ppmIntegration of the peak at 5.85 ppm (based on the amide proton), or; 2) Integration of the peak at 1.34 ppmIntegration of the peak at 1.04 ppm (based on the methyl proton in the alanine part).

(42) Using protocol described in FIG. 2, a continuous technology scale is described on Table 4.

(43) TABLE-US-00004 TABLE 4 Materials used for continuous process. Molar Reagents M.W. g mol d mL ratio Compound (G) 618.83 150.00 0.242 1.000 1.00 Formic acid 46.03 565 12.28 1.220 463 50.65 Toluene 92.14 275 2.98 0.870 316 12.30 (1 charge) Toluene 92.14 275 2.98 0.870 316 12.30 (2 charge) Theoretical products Compound (H) 564.74 136.89 0.242 1.00 Isobutene 56.11 13.60 0.242 1.00 CO.sub.2 44.01 10.67 0.242 1.00 1) Charging 1 L round-bottomed flask with 0.565 kg of formic acid; 2) Maintaining the temperature at 25 C.; 3) Purge a 1 L round-bottomed flask with N.sub.2; 4) Charging the 1 L round-bottomed flask with 0.15 kg of compound (G), and maintaining the temperature at 25 C.; 5) Heating the unit 1 L round-bottomed flask to 30 C.; 6) Reacting in the unit 1 L round-bottomed flask via deprotection, for an additional 5 h; 7) Final temperature of the batch is 30 C.; 8) QC-Test the material in the unit 1 L round-bottomed flask is performed in 30 min, and the specification obtained shows: (G)<2%.

(44) If the specification is not met, the test is continued for 1 h more and repeated. 9) Distilling the batch in the unit 1 L round-bottomed flask. 10) The bottom pressure is 80 mm-Hg and the maximum temperature is 40 C. 11) Distilling about 65% of the initial mass; 12) -Charging a 1 L round-bottomed flask with 0.275 kg of toluene. 13) Distill the batch in the unit 1 L round-bottomed flask; 14) The bottom pressure is 65 mm-Hg, and the maximum temperature is 40 C. 15) Distill about 63% of the initial mass; 16) Charging a 1 L round-bottomed flask with 0.275 kg of toluene; 17) Distilling the batch in unit 1 L round-bottomed flask; 18) The bottom pressure is 50 mm-Hg, and the maximum temperature is 40 C. 19) Distilling about 60% of the initial mass; 20) Transferring contents of the unit 1 L round-bottomed flask to a 5 L round-bottomed flask; 21) Transferring 100% of vessel contents; 22) Cooling a unit 5 L round-bottomed flask to temperature ranging from 5 C.; 23) Charging the 5 L round-bottomed flask with 1.99 kg of AcOEt; 24) Maintaining the temperature at a range from 0 C. to 10 C.; 25) Charging the 5 L round-bottomed flask with 1.09 kg of 7.2% weight NaCl solution; 26) Maintaining the temperature at a range from 5 C.; 27) Extracting in the unit 5 L round-bottomed flask over 10 min; 28) The lower layer stream, named water phase from washing, is sent to waste. 29) Charging a 5 L round-bottomed flask with 1.974 kg of AcOEt; 30) Maintaining the temperature at a range from 5 C.; 31) Transferring 100% of vessel contents of the unit 5 L round-bottomed flask to Tank 1; 32) Charging a 1 L flask with 0.56 kg of ethanol; 33) Maintaining the temperature at 25 C.; 34) Charging 1 L flask with 0.0295 kg of (2E)-but-2-enedioic acid; 35) Maintaining the temperature at 25 C.; 36) Transferring 100% of vessel contents of the unit 1 L flask to Tank 3; 37) Continuously reacting the mixture from unit Tank 1 in unit CSTR 1 via reaction neutralization. 38) The mixture feed rate is 1.097 kg/h. 39) The stream is named PL37 formate in AcOEt to continuous section. 40) The final temperature is 5 C. 41) The product stream, named biphasic mixture from neutralization, is sent to settler. 42) Continuously add a solution of 2% NaOH by weight in water from Tank 2 at a rate of 0.348 kg/h and the feed is named 2% NaOH to continuous section; 43) Extracting continuously the mixture from CSTR 1 in the unit Settler; 44) The top layer, named PL37 organic phase from neutralization, is sent to CSTR 2. 45) The bottom layer is sent to waste. 46) Continuously reacting the mixture from settler in unit CSTR 2 via reaction salification with a solution 5% fumaric acid by weight in EtOH. 47) The final temperature is ranging from 5 C. 48) The product stream is sent to Tank 5. 49) Continuously adding the material from tank 3 at a rate of 0.142 kg/h, and the feed is named fumaric acid solution to continuous salification; 50) In order to reach the steady state, the continuous apparatus was operated for 20 min, before starting to collect the compound (I) solution in Tank 5. The amounts of each solution used for reaching the steady state are in table below.

(45) TABLE-US-00005 TABLE 5 Amount of solution used to performed continuous formation of compound (I) in Tank 1 to 3. Solution Amount (g) F1: solution of 3.3% by weight in compound (H) in 362 AcOEt in Tank 1 F2: solution of 2% NaOH by weight in water in Tank 2 120 F4: solution 5% fumaric acid by weight in EtOH 48

(46) Then, the continuous apparatus was operated for 3.45 h. The input and output streams are outlined in table below.

(47) TABLE-US-00006 TABLE 6 Input/Output stream in continuous formation of compound (I) in Tank 1 to 5. Amount Flow rate (g) (g/h) Input Stream F1: solution of 3.3% by weight in 3778 1095 compound (H) in AcOEt in Tank 1 F2: solution of 2% NaOH by weight 1201 348 in water in Tank 2 F4: solution 5% fumaric acid by 492 142 weight in EtOH Output Stream Compound (I) in solution in Tank 3 4142 1201 Water phase from neutralization to 1294 375 waste in Tank 4 51) Distilling continuously the mixture from unit Tank 5 in unit thin film evaporator. The jacket temperature is 40 C. The residual pressure is 50 mm-Hg. The overhead temperature condenser is 5 C. 52) Distillate stream is sent to waste, and bottom stream, is sent to a 3 L round-bottomed flask.

(48) TABLE-US-00007 TABLE 7 Input/Output stream in continuous formation of Compound (I) in Tank 5 to 7. Amount Flow rate (g) (g/h) Input Stream Solution of Compound (I) in Tank 5 4142 1593 Output Stream Concentrated solution of Compound 500 192 (I) in Tank 6 Distilled solvents in Tank 7 3642 1401 53) Distill the batch in unit 3 L round-bottomed flask. The overhead is sent to waste. The bottom pressure is 100 mm-Hg, and the maximum temperature is 30 C. 54) Cooling the unit 3 L round-bottomed flask to temperature ranging from 20 C. 55) Charge the 3 L round-bottomed flask with 1.56 kg of diisopropyl ether, 56) The charge time is 70 min. 57) The seed is charged to crystallization 58) Maintaining the temperature ranging from 20 C. 59) Cooling unit 3 L round-bottomed flask to a range from 5 C. 60) Crystallizing the batch in the unit 3 L round-bottomed flask, during 3 h. 61) Filtering the batch from the unit 3 L round-bottomed flask in filter. 62) The transfer time of the slurry is 1 h, and the mother liquor is sent to waste. 63) Washing the cake in unit filter 2 times, in particular for each washing, using 0.10 kg of diisopropyl ether. 64) Transferring 100% of vessel contents of the unit filter to dryer. 65) Drying the batch in unit dryer for an additional time of 16 h, at temperature ranging from 25 C., and the drying pressure is 50 mm-Hg. 66) Transferring contents of the unit dryer to storage. 67) The transfer stream is named dried PL37 fumarate, which is obtained in 118 g, and with overall yield of 84% starting from compound (G).