Development and optimization of a new synthetic process for lorcaserin

Bioorganic & Medicinal Chemistry 26 (2018) 977–983

Contents lists available at ScienceDirect

Bioorganic & Medicinal Chemistry journal homepage: www.elsevier.com/locate/bmc

Development and optimization of a new synthetic process for lorcaserin Jérôme Cluzeau a,⇑, Gaj Stavber b a b

Lek Pharmaceuticals d. d., Sandoz Development Center Slovenia, API Development, Kolodvorska 27, 1234 Mengeš, Slovenia Lek Pharmaceuticals d. d., Sandoz Development Center Slovenia, Verovškova 57, 1526 Ljubljana, Slovenia

a r t i c l e

i n f o

Article history: Received 21 September 2017 Revised 27 November 2017 Accepted 4 December 2017 Available online 9 December 2017 Keywords: Active pharmaceutical ingredient Friedel-Craft reaction Racemization Process optimization

a b s t r a c t A two-step process to synthesize racemic lorcaserin was developed from 2-(4-chlorophenyl)ethanol via formation of bromide or tosylate derivatives. These derivatives were reacted with allylamine in neat conditions to provide pure N-(4-chlorophenethyl)allylammonium chloride. This compound was cyclized in neat conditions using aluminum or zinc chloride to give racemic lorcaserin. After resolution of enantiomers, the wrong enantiomer was racemized and recycled to give new R-lorcaserin. Ó 2017 Elsevier Ltd. All rights reserved.

1. Introduction The price of drugs is a major challenge in today’s world; with an ageing population and budget restrictions on national health insurers. Obesity is one of the main concerns that severely affects millions of people worldwide, and the number of obese people is increasing considerably. As well as changes to lifestyle, pharmacotherapy is also needed for successful treatment. This paper presents an example of an API process optimization related to (R)-8chloro-1-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine, also known as lorcaserin, which is one of the few drugs currently on the market for the treatment of obesity.1–3 Several synthetic strategies and routes to lorcaserin and its derivatives are known so far,1,4–9 but there is still interest to develop innovative, simple, more environmentally friendly and overall more cost-effective industrial processes for its preparation. The known routes are adversely affected either by their the use of protecting groups with low efficiency,1,5 or the use of some hazardous and toxic solvents and reagents (DMA,8,9 SOCl2,6–9 PBr3,7 HBr10 or BH31,4,6,8).

2. Process development A new process was designed from 2-(4-chlorophenyl)ethanol 1. Its aim is to be simple and economic with a 4-step process to the final (R)-lorcaserin (R-LCS), where sustainable attributes like sol⇑ Corresponding author. E-mail address: [email protected] (J. Cluzeau). https://doi.org/10.1016/j.bmc.2017.12.009 0968-0896/Ó 2017 Elsevier Ltd. All rights reserved.

vent-free conditions and recycling of solvents and undesirable enantiomer were also taken into consideration. In previous work done on lorcaserin, the first step of the processes with starting material 1 proceeded via conversion of this compound into the chloride using thionyl chloride in a DMF/toluene mixture1 or into bromide 2 using expensive PBr37 or dangerous gaseous HBr.10 Alternatively, Compound 4 maybe obtained from protection of 2-(4-chlorophenyl)ethylamine as a carbamate or an acetate followed by alkylation of the resulting amide or carbamate with allylbromide.1,5 None of these methods satisfied us and we looked for a safer and simpler process. Two possible pathways (A and B) were found, as described in Fig. 1. i) a two-step process via bromination of alcohol in an aqueous medium followed by substitution with allylamine (path A), ii) a telescoped process involving the formation of a tosylate followed by reaction with allylamine (path B). The pathway A utilized a known protocol of hydrobromination in aqueous HBr at 85 °C which gave the desired brominated material in good yield and purity after a simple extraction in heptane.11,12 The reaction was easily scalable and the heptane used for extraction of compound 2 was recycled. Compound 2 was then easily converted to mono allylamine by reacting with a large excess of allylamine in neat conditions at reflux to provide the compound 4. The disubstituted allylamine compound 5 was also formed during the process and the amount of allylamine was directly linked to the ratio between 4b and 5. Therefore, a minimum of 4 equivalent of allylamine was needed but optimum was reach at 6–7 equivalents to get a good yield of 4b (see Table 1). Isolation was first performed in DCM but was later replace by EtOAc despite lower yield to increase sustainability of the process. Purifi-

978

J. Cluzeau, G. Stavber / Bioorganic & Medicinal Chemistry 26 (2018) 977–983

Fig. 1. New synthetic routes to compound 4.

cation of the mixture was done by simply mixing of the solid material in isopropyl acetate at room temperature, followed by filtration of the solid. Pure compound 4b was always obtained after this purification, even when low yield was obtained (see Table 2, entry 1). During larger scale experiments, compound 4b was isolated at a yield of 83% on a 200 g scale. In large-scale experiments, the excess of allylamine as well as isopropyl acetate used during the purification could be recycled by distillation. The second pathway (B) included the conversion of alcohol 1 to the tosylate 3 in various conditions (see Table 2). The reaction was first done in pyridine. The tosylate formation was done at room temperature and the alkylation at 50 °C. This protocol lead to a low amount of compound 4. To improve the isolated yield, tosylate formation was then carried out with Et3N/DMAP as a base in dichloromethane. The subsequent alkylation was done either by addition of allylamine and heating to reflux or by concentration of the reaction to an oil which was diluted in allylamine and heated to reflux. The fact that DCM could react with nucleophile to form impurities and that concentrated reaction would improve the conversion, we performed alkylation in neat conditions and obtained a yield three times higher (63%) than the one in dichloromethane (20%). Finally, the best conditions for the tosylate formation were found using powdered KOH in THF. After removal of THF, alkylation was performed in neat conditions and reaction led to product 4b in high yield (89%). The synthetic path A was finally chosen. During the scale-up, the synthesis of compound 4b via bromination and intermediate 2 appeared to be more robust and reproducible than path B via tosylate formation. A possible explanation was that tosylate formation with KOH powder was very dependent on mixing due to heterogenous nature of the reaction and on the hygroscopic nature KOH powder. This is indeed a classical issue of mass transfer problem. It is likely due to the particle size of KOH and the solid-liquid interface. The early screening of the Friedel-Craft cyclization was evaluated using some Brønsted acids or Lewis acids such as aluminum chloride as an activator to evaluate capabilities of each acid. Brønsted acids, used as solvents, led to recovered compound 4 in case of TFA and polyphosphoric acid (Table 2, entry 1 and 4). Reac-

tion with sulfonic acids showed increased reactivity but led primarily to undesired compounds 7 and 8 with no trace of cyclization (Fig. 2). Experiments with aluminum chloride were done in similar conditions (Table 3, entry 5) as described in literature5 but only a small amount of undesired compound 7 was obtained. Replacing dichlorobenzene with sulfolane as solvent showed even less reactivity and untouched compound 4 was recovered. Experiment in heptane (Table 3, entry 7) lead mainly to the desired product together some starting material and unknown impurities. During this experiment, two phases were observed, a coloured phase on the bottom and the colourless heptane on the top. We decided to remove the solvent and to perform the reaction in neat conditions as previously described by Perchonock, but without addition of ammonium chloride since our compound already contained an ammonium chloride.13 During the heating phase of the experiment, the mixture of powders (AlCl3 + 4b) melted around 80–85 °C and the reaction was done in the molten phase. The mixture was next diluted with brine and product 6 was isolated by extraction in brine with dichloromethane and recrystallization from acetone, the desired racemic cyclic compound 6 was obtained in good yield and purity (entry 8) We were curious to screen different metals and evaluate which other Lewis acids could use in this cyclization reaction. We tested the most common Lewis acid (boron trifluoride, Bi(III), Ce(III), Cu(I) and Cu(II), Fe(II) and Fe(III), In(III), Mg, Mn, Sc(III), Ti(III) and Ti(IV), Zn and Y(III)).14 Most of them did not show any reactivity, even though they were able to form a molten phase. The copper species (Table 4, entries 5–7) triggered the consumption of starting compound 4, leading to an unidentified mixture of compounds. Only zinc chloride (Table 4, entry 16) showed a good reactivity and gave a full conversion to product 6 in good purity. Interestingly, the same experiment performed with the free amine 4a gave no conversion and recovered compound 4. Similarly, the reaction of compound 4b with zinc triflate also resulted in no conversion (entry 17). Zinc chloride together with TMSCl is known in literature to catalyze Friedel-Craft reactions on activated systems such as phenols and styrenes15 but as far as we know such a reaction using non-activated olefins and aromatic ring is not common.

3. Process optimization The parameters and kinetics16 of the reaction were further studied for the aluminum chloride process because of the high price of anhydrous zinc chloride. First, we evaluated the amount of aluminum chloride needed to obtain full conversion to product 6 (Table 5). The amount was varied from 0.5 to 1.75 M equivalent. The results showed that the process required an excess of AlCl3, over 1 equivalent. This was in accordance with the formation of ionic liquid between the ammonium chloride and the aluminum chloride known to promote olefin condensation.17,18 Temperature could also have strong impact on the process since the reaction takes place in the molten phase and occurs at around

Table 1 Experimental data for path A. Entry

1 2 3 4 5

Eq allylamine

4 5 6 7 8

Isolation in DCM

Isolation in EtOAc a

Yield

Crude HPLC

Final purity

69% 81% 83% 86% 87%

84,7% 90,2% 92,0% 92,1% 92,5%

>99% >99% >99% >99% >99%

Experiments performed at 54 °C. a. final HPLC purity after mixing crude compound 4b in iPrOAc.

Yield

HPLC Purity

73%

>99%

74% 73%

>99% >99%

979

J. Cluzeau, G. Stavber / Bioorganic & Medicinal Chemistry 26 (2018) 977–983 Table 2 Synthesis of compound 4b via tosylate formation. Entry

Base

Eq base

Eq TsCl

Solvent 1a

Solvent 2

Yieldb

1 2 3 4 5

Et3N/DMAP Et3N/DMAP / / KOH powder

1.2/0.1 1.2/0.1 / / 4

1.1 1.1 1.1 1.3 1.3

DCM DCM pyridine pyridine THF

DCM allylamine pyridine pyridine allylamine

20% 63% 28% 29% 89%

a: Solvent 1 refers to reaction with TsCl and solvent 2 to reaction with allylamine (4 eq). b: isolated yield after purification in iPrOAc. Purity > 98% by 1H NMR for all entries after slurring in iPrOAc.

Fig. 2. cyclization of compound 4b.

Table 3 Testing Friedel-Craft cyclization on compound 4b. Entrya

Activator

Equivalent

Solvent

1 2 3 4 5 6 7 8

/ / / MeSO3H AlCl3 AlCl3 AlCl3 AlCl3

/

TFA H2SO4 PPA / DCB sulfolane heptane /

/ / 1.75 1.75 1.75 1.75

Isolated mass

74 84

1

H NMR crude ratio

4

6

Impurities

100 33 100 55 67 100 2 5

0 0 0 0 0 0 65 95

0 66b 0 45 33b 0 33 0

a: All experiments were performed at 125 °C for 6 h. b: impurities mainly composed of compound 7.

Table 4 Metal screening for Friedel-Craft cyclization. Entrya

1c 2 3 4 5 6 7 8 9 10 11 12 13 14 15 13 14 15 16d 17 18 19

Starting compound

4b 4b 4b 4b 4b 4b 4b 4b 4b 4b 4b 4b 4b 4b 4b 4b 4b 4b 4b 4a 4b 4b

Activator

BF3OEt2 BiCl3 Bi(OTf)3 Ce(OTf)3 CuCl CuBr2 CuOAc2 FeCl3 FeBr3 FeOAc2 InCl3 MgCl2 Mg(OTf)2 MnCl2 Sc(OTf)3 ScCl3 TiCl3 TiCl4 ZnCl2 ZnCl2 Zn(OTf)2 Y(OTf)3

1

H NMR ratio

4

5

Impurities

100 100 100 100 0 5 30 100 100 100 100 100 100 100 100 100 100 100 0 100 100 100

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 90 0 0 0

0 0 0 0 100c 95c 70c 0 0 0 0 0 0 0 0 0 0 0 10 0 0 0

a: Experiments were done neat with compound 4a or 4b (1 mmol), 1.75 eq of Lewis acid at 125 °C for 5 h.: 3.5 eq of BF3.OEt2. c: unidentified products. d: crude yield of 87%.

80 °C. The temperature was varied from room temperature to 125 °C and it appeared that the starting material was consumed even at room temperature for solid-solid interaction, to form compound 7 rather than compound 6. Once the molten phase was reached at around 80–85 °C, the desired product also started to be formed

(Table 6, entry 3). The reaction got selective at 105 °C where no more product 7 was observed (Table 6, entry 5). These results suggested that compound 7 is the first intermediate formed during the reaction which is then cyclized under normal Friedel-Craft conditions via further AlCl3 activation. When compound 7b (chloride

980

J. Cluzeau, G. Stavber / Bioorganic & Medicinal Chemistry 26 (2018) 977–983 Table 5 Effect of aluminum chloride stoichiometry. Entrya

Equivalent AlCl3

1 2 3 4 5

0.5 0.75 1 1.25 1.75

Yield

/ / / 48 86

1

H NMR ratio 4b

6b

100 100 100 1 0

0 0 0 99 100

a: Experiments done on 1 mmol scale at 125 °C for 6 h from compound 4b. b: 1H NMR ratio.

Table 6 Temperature effect of cyclization of compound 4b. Entry

1 2 3 4 5 6 7

T °C

25 55 85 95 105 115 125

Isolated mass

90 91 91 86 84 83 86

1

H NMR ratio

4

6

7

83 63 69 1 0 0 0

0 0 13 49 100 100 100

17 37 18 50 0 0 0

Experiments done on 1 mmol scale from compound 4b with 1.75 equivalent AlCl3.

counterion, X = Cl) was reacted in the same reaction conditions (neat AlCl3, 125 °C), compound 6 was obtained in similar yield and quality as compound 4b (see Fig. 3).1 To evaluate the importance of obtaining a clean hydrochloride salt during the synthesis of 4 or to ascertain if the presence of the bromide ion could interfere in the process, we studied the influence of counterions on the process. We next determined which counterion is optimal for the process. First, pure bromo counterion 4c (X = Br) was prepared and evaluated. It gave the desired product 6 as from compound 4b with slightly lower yield. This result confirmed our first choice of the chloride salt but ensure us that small contamination with bromide salt won’t be critical. The free base 4a was then reacted and the desired product was as well obtained in similar yield and quality as that from hydrochloride salt 4b. This suggested that counterions may not have influence when AlCl3 is used. To obtain more insight about this, other salts were prepared. Methanesulfonate and trifluoroacetate salts 4d and 4e were successfully isolated as solids. The reaction of compound 4d (Table 6, entry 3 and 4) gave some small amount of desired compound 6 as well as known compound 8. This compound was probably obtained from less reactive intermediate 9 after aqueous work-up. On the opposite, salt 4e (Table 7, entry 5 and 6) didn’t convert at all and unreacted compound 4 was fully recovered unreacted. These results showed the importance of counterions in the reaction mechanism. Salts 4b and 4c reacted first to form the ionic salt of compound 4 having AlCl3X (X = Cl or Br) as counterion. This ionic salt react to give compound 7 complexed with AlCl3. A second AlCl3 molecule include the FriedelCraft cyclization, generating one molecule of HCl and releasing one AlCl3 involved in a next cycle (see Fig. 4). In the case of com-

pound 4a, some small amount of HCl was most probably present in the aluminum chloride to form an in-situ small amount of salt 4b. The catalytic amount of HCl was then released after each cyclization, enabling the reaction to proceed. This mechanism didn’t occur in cases of salts 4e but in case of 4e, the reaction seems to proceed until intermediate 9 which is much more difficult cyclize via Friedel-Craft cyclization. Compound 9 is hydrolyzed during work-up and compound 8 is isolated (see Table 7 and Fig. 4). 4. Racemization The racemic lorcaserin obtained was then converted to tartrate salt and recrystallized according to the literature, providing the Rlorcaserin.6 Since the process was optimized to avoid losses, we decided to look for a method to recycle the S-lorcaserin. Recycling of unwanted enantiomer which was collected after resolution would provide an entry to a more cost-efficient process by reducing wastes (aluminum and acidic water wastes from bromation and Friedel-Craft steps) and material/energy consumption eventhough an extra step is added. Two methods were screened: the radical alkali metals (Li or Na in naphthalene) and the use of strong bases (tBuOK or NaOMe). Because of limitations or issues with the radical racemization processes regarding metal traces and toxic aromatic solvents such as naphthalene in the final API, we focused on the use of strong bases in polar aprotic solvents, DMSO been the less harmful of them regarding environment (Fig. 5).19 For the development of the method, pure R-lorcaserin (SM1, see Table 8) was used to better evaluate the efficiency of the racemization method, as well as the possible generation of impurities. Two

Fig. 3. Preparation of compound 6 from compounds 4b or 7b (experiments done at 125 °C with 1,75 eq. of AlCl3).

981

J. Cluzeau, G. Stavber / Bioorganic & Medicinal Chemistry 26 (2018) 977–983 Table 7 Effect of the counterion on cyclization of compound 4. Entrya 1 2 3 4 5

Starting compound 4b 4c 4a 4d 4e

counter ion Cl Br / MeSO3 CF3CO2

Eq. AlCl3

Isolated yield b

1.75 1.75 1.75 1.75 1.75

98 (73) 74 85 n.a. n.a.

Conversion (1H NMR)

HPLC purity

100 100 100 10d 0

94 (98)b 74 79 n.a. n.a.

a: Experiments done on 10 mmol scale except entry 1 and 2 done on 430 and 40 mmol respectively. b: HPLC purity after digestion in acetone. c: 42% of compound 8 by 1H NMR. d: 14% of compound 8 by 1H NMR.

Fig. 4. Proposed mechanism for the cyclization process. Probable structure of intermediate 9 when X = MeSO3.

Fig. 5. Resolution/racemization process of compound 6.

different bases were tested: sodium hydroxide powder and potas-

sium tert-butoxide powder. The racemization was influenced by both concentration of the reaction and excess of base. To reach full racemization, a large excess of sodium hydroxide (2 eq), a high concentration (3M) and a long reaction time (72 h) were needed at 120 °C. The amount of impurities was significantly higher than in the starting material. The potassium tert-butoxide required a much lower amount of reagent (0.5 eq) and reaction time (2 h) to reach full racemization which was as such a safer process but the amount of impurities were more pronounced (Table 8, entry 6). The amount of reagent was next decreased (0.25 equivalent) in the hope for a cleaner reaction. A decrease of temperature (60 °C) also helped to mitigated the degree of decomposition. Further lowering of temperature to 50 °C led to incomplete racemization while lowering of the reagent amount required a higher temperature and led to lower purity. We use our best conditions (Table 8, entry 8) to convert a large amount of compound S-6 isolated from crystalliza-

Table 8 racemization of lorcaserin. Entrya

S.M.

Conc (M)

Eq base

Base

T °C

Time (h)

SM1b SM2b 1 2 3 4 5 6 7 8 9 10 11 12 13

SM1 SM1 SM1 SM1 SM1 SM1 SM1 SM1 SM1 SM1 SM1 SM1 SM2

3 1 2 3 3 1 1 1 1 1 1 1 1

1 2 2 2 2 0.5 0.25 0.25 0.25 0.15 0.15 0.15 0.25

NaOH NaOH NaOH NaOH NaOH tBuOK tBuOK tBuOK tBuOK tBuOK tBuOK tBuOK tBuOK

120 120 120 120 120 80 80 60 50 100 100 80 60

72 24 24 24 48 2 2 2 2 2 9 16 2

ee%

HPLC purity

100% 38%

99.8% 95.4%

32% 34% 14% 8% 0% 0% 0% 2% 28% 8% 0% 20% 0%

97.1% 99.0% 98.7% 98.5% 98.5% 90.3% 97.5% 99.2% 99.8% 99.1% 96.4% 99.5% 95.5%

Yield

77% 88% 94% 99% 91% 76% 91% 96% 92% 86% 93% 86% 92%

a. Experiments were performed on 2 mmol scale in DMSO. b. SM1 is a pure R-6 and SM2 is a representative sample of S-6 isolated from resolution crystallization mother liquor.

982

J. Cluzeau, G. Stavber / Bioorganic & Medicinal Chemistry 26 (2018) 977–983

tion mother liquor (SM2). Racemic lorcaserin was obtained (entry 13) and used to produce new tartrate salt and R-lorcaserin. It is worth mentioning that the newly developed racemization methodology strongly increased the overall yield of the overall process for at least 20–30% and consequently led to a significantly lower total production cost of final API. Stability of DMSO could be a safety concern. Safety issues were well reported in acidic conditions.20–22 The utilization of DMSO in basic conditions is more common and in general with no safety concern even at higher temperature23–26 however unexplained runaway have been reported.27,28 To ensure the safety of our process, it is proceeding with tBuOK, reported not to lead to explosive decompoistion,27 it is running at relatively low temperature (60 °C) under nitrogen with catalytic amount of tBuOK (less than 2 mol% tBuOK comparing to DMSO). Process is far from the known runaway conditions generally using quantitative amount of base or metal (NaH or Na), high temperature (200 °C) or performed in presence of oxygen.27,28 Furthermore, racemization is fast (2h) with a ratio DMSO/lorcaserin/tBuOK of 50/4/1, we can assume that lorcaserin benzylic proton is more acidic than DMSO preventing formation of dimsyl ion in significant amount. 5. Conclusions Efficient and economic process was successfully developed for lorcaserin. This synthetic route gives access to racemic lorcaserin and involves 2 simple chemical steps from commercially available routine starting materials to racemic lorcaserin followed by diastereomeric crystallization provide optical pure target API (purity > 99.8%). Insight into the crucial synthesis step - a Friedel-Craft reaction of an allyl ammonium chloride salt in the presence of aluminum or zinc chloride under neat conditions – were gathered. We also report a more sustainable and economic process in the final optical resolution stage by developing an efficient racemization technology. This led to a more economical overall process by significantly lowering the raw material cost in comparison to the best known prior art. 6. Experimental 6.1. Synthesis of 2-(4-chlorophenyl)ethylbromide 2 2-(4-Chlorophenyl)ethanol (25 g, 160 mmol) was suspended in aqueous HBr 48% (150 mL, 8 eq) and solution was heated to 85 °C for 24 h. Solution was cooled down to room temperature and diluted with heptane (300 mL) and water (150 mL). Phases were separated and water phase was re-extracted twice with heptane (2  100 mL). Combined organic phase was dried on Na2SO4, filtered and concentrated to give compound 2 (30.2 g, 86%) corresponding to known literature compound.10 1 H NMR (500 MHz, CDCl3, ppm) d 7.28 (d, J = 8.5 Hz, 2H), 7.17 (d, J = 8.5 Hz, 2H), 3.56 (d, J = 7.4 Hz, 2H), 3.15 (d, J = 7.4 Hz, 2H); 13 C NMR (125 MHz, CDCl3, ppm) d 32.6, 38.5, 128.7, 130.0, 132.7, 137.2. 6.2. Synthesis of N-(4-chlorophenethyl) allylaminium chloride 4b from compound 2 2-(4-Chlorophenyl) ethylbromide 2 (350 g, 1.59 mol) was dissolved in allylamine (910 mL, 7.6 eq) and the solution was heated to reflux overnight. The solution was cooled down to room temperature. Allylamine was distilled off under reduced pressure. Oil was dissolved in EtOAc (350 mL) and solution was concentrated. Solution was dissolved in EtOAc (1 L) and solution was washed with 4

M NaOH (450 mL), with 1:1 mixture of 1 N HCl/brine (2000 mL). Acidic water phase was re-extracted with EtOAc (2  2 L). Combined organic phase was concentrated. Solid was suspended in isopropyl acetate (1 L) and stirred at room temperature for an hour. Solid was filtered and washed with some isopropyl acetate (2  250 mL). Solid was dried to give compound 4b (322 g, 87%). 1 H NMR (500 MHz, CDCl3, ppm) d 9.89 (bs, NH), 7.28 (d, J = 8.5 Hz, 2H), 7.18 (d, J = 8.5 Hz, 2H), 6.11 (m, 1H), 5.51 (d, J = 17.0 Hz, 1H), 5.48 (d, J = 10.2 Hz, 1H), 3.63 (d, J = 7.0 Hz, 2H), 3.23 (m, 2H), 3.13 (m, 2H); 13C NMR (125 MHz, CDCl3, ppm) d 31.6, 47.5, 49.7, 124.4, 127.4, 129.1, 130.1, 133.1, 134.8; IR (neat): m = 3436, 2979, 2942, 2801, 2765, 2710, 2641, 2431, 1495, 1446, 1425, 1409, 1339, 1090, 1016, 994, 944, 835, 806 cm 1.

6.3. Synthesis of N-(4-chlorophenethyl) allylaminium chloride 4b from compound 1 Compound 1 (30.4 mL, 1 eq) was dissolved in dry THF (380 mL). Powdered KOH (50.4 g, 4 eq) was added and solution was cooled down to 10 °C. p-Toluenesulfonyl chloride (55.75 g, 1.3 eq) was added slowly. Reaction mixture was warmed-up to room temperature and stirred overnight. Reaction mixture was filtered on CeliteÒ. Solution was concentrated under vacuum to give an oil. Oil was dissolved in allylamine (67.4 mL, 4 eq) and solution was heated to 50 °C and stirred overnight. Solution was concentrated, diluted with toluene (300 mL) and NaOH 2 N (300 mL). Phases were separated and water phase was re-extracted with toluene (100 mL). Solution was extracted three times with HCl 1N (3  300 mL). Combined HCl phase was extracted three times with dichloromethane (3  150 mL). Combined organic phase was dried over MgSO4, filtered and concentrated to a solid. Solid was suspended in iPrOAc (50 mL) and was stirred overnight. Solid was filtered to give desired compound 4b (37.4 g, 71.7%).

6.4. Synthesis of N-(4-chlorophenethyl) allylaminium methanesulfonate 4d from compound 4b Compound 4b (1 g) was dissolved in dichloromethane (30 mL) and solution was washed with saturated Na2CO3 solution (20 mL). Organic phase was concentrated. Oil was dissolved in THF (50 mL) and methanesulfonic acid (0.28 mL, 1 eq.) was added. Solution was stirred for 15 min and concentrated. Oil was diluted in iPrOAc (20 mL). Hexane (20 mL) was added slowly and solution was stirred for 30 min. Solid was filtered and dried to give the desired product. (m = 1.1 g, 88%). 1 H NMR (500 MHz, CDCl3, ppm) d 8.99 (br s, 1H), 7.25 (m, 2H), 7.17 (d, 2H), 6.00 (m, 1H), 5.46 (dd, J = 1.0 Hz, J = 17.0 Hz, 1H), 5.44 (dd, J = 1.0 Hz, J = 10.2 Hz, 1H), 3.65 (d, J = 7.0 Hz, 2H), 3.10 (s, 4H), 2,80 (s, 3H).

6.5. Synthesis of N-(4-chlorophenethyl) allylaminium trifluoroacetate 4e from compound 4b Compound 4b (1 g) was dissolved in dichloromethane (30 mL) and solution was washed with saturated Na2CO3 solution (20 mL). Organic phase was concentrated. Oil was dissolved in THF (50 mL) and TFA (0.33 mL, 1 eq.) was added. Solution was stirred for 30 min and concentrated. Oil was diluted in MTBE (3 mL). Heptane (15 mL) was added slowly and solution was stirred overnight. Solid was decanted and dried to give the desired product. (m = 0.9 g, 68%). 1 H NMR (500 MHz, CDCl3, ppm) d 7.28 (d, J = 8.5 Hz, 2H), 7.12 (d, J = 8.5 Hz, 2H), 5,89 (m, 1H), 5.44 (d, J = 17.0 Hz, 1H), 5.41 (d, J = 10.2 Hz, 1H), 3.54 (d, J = 7.0 Hz, 2H), 3.09 (m, 2H), 2,97 (m, 2H).

J. Cluzeau, G. Stavber / Bioorganic & Medicinal Chemistry 26 (2018) 977–983

6.6. 8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-3-ium chloride 6 Caution: Quenching reaction containing AlCl3 can release a large quantity of HCl gas. This HCl gas can be (depending on the scale) quenched by bubbling gas in concentrated solution of Na3PO4 or NaOH or by using HCl scrubbing for larger scale (NaOH, calcium carbonate). N-(4-chlorophenethyl) allylaminium chloride 4b (100 g, 431 mmol) and aluminum chloride (100 g, 1.75 eq) were added to a 1L reactor. Solids were heated to 125 °C for 5 h. Solution was cooled down to 90 °C and transferred slowly (by portions, keeping the reaction mixture at 90 °C) to a cooled ( 5°C) stirred brine solution (0,5 L). (On larger scale thermostated valves and pipes have to be used to transfer the melt and avoid solidification of the melt and enable better control of the addition) When addition was finished and solution was at 20 °C, the solution DCM (0.5 L) was added and solution was stirred overnight. Solution was filtered on Celite. Phases were separated and water phase was re-extracted with DCM (0.15 L). Combined organic phase was dried over Na2SO4, filtered and concentrated. Solid was suspended in acetone (160 mL) and stirred for 30 min. Solid was filtrated and washed with acetone (3  60 mL). Solid was dried to give compound 6 (74.2 g, 73.5%, 98.9% HPLC purity). 1 H NMR (500 MHz, CDCl3, ppm) d 10.1 (bs, NH), 7.16 (dd, J = 2.8 Hz, ArH), 7.10 (d, J = 2.1 Hz, ARH), 7.04 (d, J = 8 Hz, ArH), 3.65 (m, 2H), 3.35 (m, 2H), 2.75–3.05 (m, 3H), 1.50 (d, J = 7 Hz, 1H); 13C NMR (125 MHz, CDCl3, ppm) d 18.1, 31.9, 34.6, 45.5, 51.4, 126.2, 127.2, 131.1, 133.4, 136.8, 144.29. IR (neat): m = 3432, 2978, 2879, 2688, 2600, 2499, 2429, 1581, 1486, 1474, 1460, 1450, 1427, 1402, 1389, 932, 876, 830, 815 cm-1. MS (CI) m/z (%): 224/226 (M+29, 30.5%/10.2%), 196/198 (100%/31.3%), 176,0 (46.1%), 160 (22.4%), 147 (10.3%). 6.7. Racemization of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-benzo [d]azepin-3-ium chloride S-6 The residue (S)-6 (0.39 g, 38% e.e.) recovered from crystallization of the mother liquor from (R)-6 was dissolved in anhydrous DMSO (2 mL). During slow heating (10 °C/min), potassium tertbutoxide (56 mg) was added. The mixture was then stirred in an inert atmosphere at 90–100 °C overnight. After the completion of the reaction, the mixture was cooled down to room temperature, diluted with brine (5 mL) and extracted with n-heptane (3  10 mL). The organic phases were washed with brine, dried over anhydrous Na2SO4 and the solvent was evaporated under reduced pressure to give racemic compound 6 (0.36 g, HPLC e.e.: 0.5%. HPLC purity: 95.5 A%).

2. 3. 4.

5. 6. 7.

8.

9.

10.

11.

12.

13.

14.

15. 16.

17. 18.

19. 20.

21.

22.

23.

24.

A. Supplementary data 25.

Supplementary data associated with this article can be found, in the online version, at https://doi.org/10.1016/j.bmc.2017.12.009.

26. 27.

References 1. Smith B, Smith J, Tsai J, et al. Discovery and structure activity relationship of (1R)-8-Chloro-2,3,4,5-tetrahydro-1-methyl-1H-3-benzazepine (Lorcaserin), a

28.

983

selective serotonin 5-HT2C receptor agonist for the treatment of obesity. J Med Chem. 2008;51:305–313. Daubresse M, Alexander G. The uphill battle facing anti-obesity drugs. Int J Obesity. 2015;39:377–378. Manning S, Pucci A, Finer N. Pharmacotherapy for obesity: novel agents and paradigms. Therap Adv Chronic Dis. 2014;5:135–148. Smith B, Smith J, Tsai J, et al. Discovery and SAR of new benzazepines as potent and selective 5-HT2C receptor agonists for the treatment of obesity. Bioorg Med Chem Lett. 2005;15:1467–1470. Zhu Q, Wang J, Bian X, Zhang L, Wei P, Xu Y. Novel synthesis of antiobesity drug lorcaserin hydrochloride. Org Process Res Dev. 2015;19:1263–1267. Burbaum BW, Gilson CA, Aytes S, Estrada SA, Sengupta D, Smith B, Rey M, Weigl U. Process for preparation of 3-benzazepines. WO Patent P.N.:2005019179. Weigl U, Porstmann F, Straessler C, Ulmer L, Koetz U. Processes for preparing (R)-8-chloro-1-methyl-2,3,4,5-tetrhydro-1H-3-benzazepine and intermediates related thereto. WO Patent P.N.:2007120517. Gharbaoui T, Tandel SK, Ma Y, Carlos M, Fritch JR. Processes for preparing (R)-8chloro-1-methyl-2,3,4,5-tetrhydro-1H-3-benzazepine and intermediates thereof. WO Patent P.N.:2008070111. Demattel J, Carlos M, Castro R, Chuang T-H, Hadd M, Lu X-X, Macias M, Shaw SM, Processes for the preparation of 5-HT 2C receptor agonists. WO patent P. N.:2010148207. Carlos M, Castro R, Ghar-Baoui T, Lu X-X, Ma Y-A, San Martin N. Processes for the preparation of intermediates related to the HT2c agonist (R)-8-chloro-1methyl-2,3,4,5-tetrahydro-1H-3-benzazepine. WO patent P.N. 2009111004. Ringstrand B, Ottmanns M, Batt JA, Jankowiak A, Denicola RP, Kaszinsky P. The preparation of 3-substituted-1,5-dibromopentanes as precursors to heteracyclohexanes. Beilstein J Org Chem. 2011;7:386–393. Uchida M, Tabusa F, Komatsu M, Morita S, Kanbe T, Nakagawa K. Studies on 2 (1H)-quinolinone derivatives as gastric antiulcer active agents. 2-(4chlorobenzoylamino)-3-[2 (1H)-quinolinon-4-yl] propionic acid and related compounds. Chem Pharm Bull. 1985;33:3775–3786. Perchonock C, Finkelstein J. Friedel-crafts cyclization of chloro-substituted (benzy1amino)propyl bromides. formation of 4-methyltetrahydroisoquinoline. J Org Chem. 1980;45:2001–2004. Rueping M, Nachtsheim B. A review of new developments in the Friedel-Crafts alkylation – from green chemistry to asymmetric catalysis. Beilstein J Org Chem. 2010;6:1–24. Lee S, Villani-Gale A, Eichman C. Room temperature catalyst system for the hydroarylation of olefins. Org Lett. 2016;18:5034–5037. Grom M, Stavber G, Drnovšek P, Likozar B. Modelling chemical kinetics of a complex reaction network of active pharmaceutical ingredient (API) synthesis with process optimization for benzazepine heterocyclic compound. Chem Eng J. 2016;283:703–716. Liu Y, Li R, Sun H, Hu R. Effects of catalyst composition on the ionic liquid catalyzed isobutane/2-butene alkylation. J Mol Cat A: Chem. 2015;398:133–139. Huang C-P, Liu Z-C, Xu C-M, Chen B-H, Liu Y-F. Effects of additives on the properties of chloroaluminate ionic liquids catalyst for alkylation of isobutane and butene. App Cat A: Gen. 2004;277:41–43. Byrne FP, Jin S, Paggiola G, et al. Tools and techniques for solvent selection: green solvent selection guides. Sustain Chem Process. 2016;4:7–31. Bollyn M. DMSO can be more than a solvent: thermal analysis of its chemical interactions with certain chemicals at different process stages. Org Process Res Dev. 2006;10:1299–1312. Wang Z, Richter SM, Gates BD, Grieme TA. Safety concerns in a pharmaceutical manufacturing process using dimethyl sulfoxide (DMSO) as a solvent. Org Process Res Dev. 2012;16:1994–2000. Wang Z, Richter SM, Bellettini JR, Pu Y-M, Hill DR. Safe scale-up of pharmaceutical manufacturing processes with dimethyl sulfoxide as the solvent and a reactant or a byproduct. Org Process Res Dev. 2014;18:1836–1842. Delhaye L, Stevens C, Merschaert A, et al. Development of a scalable process for the synthesis of trans-2-methylcyclopropanecarboxylic acid. Org Process Res Dev. 2007;11:1104–1111. Patil GD, Kshirsagar SW, Shinde SB, et al. Identification, synthesis, and strategy for minimization of potential impurities observed in Raltegravir potassium drug substance. Org Process Res Dev. 2012;16:1422–1429. Wang F, Shen J, Cheng G, Cui X. Practical access to 1,3,5-triarylbenzenes from chalcones and DMSO. RCS Adv. 2015;5:73180–73183. Dahl AC, Mealy MJ, Nielsen MA, Lyngsø LS, Suteu C. Route scouting and process development of LU AA26778. Org Process Res Dev. 2008;12:429–441. Hazards involved in the handling and use of Dimethyl Sulphoxide DMSO. Loss Prev Bull. 1993;114:9. Itoh M, Morisaki S, Muranaga K, et al. Anzen Kogaku. 1984;23:269.