Development of the Asymmetric Hydrogenation Step for Multikilogram

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Development of Asymmetric Hydrogenation Step for Multikilogram Production of Etamicastat Alexandre Arkadievitch Beliaev Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.6b00041 • Publication Date (Web): 21 Mar 2016 Downloaded from http://pubs.acs.org on March 24, 2016

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Organic Process Research & Development

Development of Asymmetric Hydrogenation Step for Multikilogram Production of Etamicastat Alexandre Beliaev* Laboratory of Chemistry, Department of Research & Development, BIAL, 4745-457 S. Mamede do Coronado, Portugal [email protected] RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required according to the journal that you are submitting your paper to) *Corresponding author. Tel: 351-22-9866100. Fax: 351-22-9866192.

ACS Paragon Plus Environment

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Table of Contents graphic


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ABSTRACT: Asymmetric hydrogenation of methyl (6,8-difluoro-2H-chromen-3-yl)carbamate is a key step in the manufacturing route to etamicastat. A development of this step including the ruthenium or rhodium catalyst screening and the influence of the catalyst preparation (isolated, preformed in solution or in situ), solvent, temperature, pressure, additive, concentration on the performance of the given ligand was discussed. Scale-up experiments for the best catalysts under optimised conditions were described.

KEYWORDS: Etamicastat, BIA 5-453, 3-aminochroman, ene-carbamate, asymmetric hydrogenation, ruthenium catalyst, rhodium catalyst, catalyst screening. Introduction Etamicastat (BIA 5-453 or (R)-5-(2-aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole2-thione hydrochloride, 1) is a novel peripherally selective dopamine β-hydroxylase (DBH) inhibitor developed by Bial - Portela & Cª, S.A. for treatment of hypertension and congestive heart failure.1 The compound was shown to be well tolerated in healthy volunteers.2 The process research for multikilogram production of etamicastat has been recently disclosed in this journal.3 Chart 1

An important part of etamicastat structure is (R)-3-amino-6,8-difluorochroman (2) which is also an intermediate in all known syntheses of the drug. After extensive route scouting, asymmetric hydrogenation of methyl (6,8-difluoro-2H-chromen-3-yl)carbamate followed by the basic hydrolysis of methyl carbamate was found to be the most convenient approach to the amine 23 (Scheme 1). In this article, a full account of the development activities for the asymmetric hydrogenation step including the catalyst screening and the optimization of various parameters, such as the catalyst preparation (pre-


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formed isolated, pre-formed non-isolated or in situ), solvent, temperature, pressure, additive and concentration, is provided. Scheme 1. Manufacturing route to amine 2a

a

Reagents and conditions: a) Ru biphosphine catalyst S/C 4000, 30 bar H2, MeOH, 80ºC, 20 h; b) Water, 2-propanol, reflux to 20ºC; c) 40% KOH, MeOH, reflux, 24 h; d) L-tartaric acid, ethanol, water, rt, 1 h. By the time of initiation of the screening program, the asymmetric hydrogenation of structurally similar tetraline- and chroman-derived ene-carbamates using Ru-BINAP and Ru-DuPhos catalysts had been described. The maximum enantiomeric excess (e.e.) values obtained with either system were up to 76% (92% for one particular substrate).4,5 Chart 2

Screening of isolated Ru catalysts For the initial tests, four ene-carbamate substrates 3, 5-7 bearing different substituents in the carboxylate group (Chart 2) were prepared.3 The study was carried out using isolated rutheniumbisphosphine-based catalysts (ligand structures in Chart 3). Chart 3


4

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Organic Process Research & Development R

R O

R

R

S

R

R'

N P

O O

R R

P

P

R

P

P

R

P

P O ( )n O

P

R

R' R'

R

N

R R' O R

RR

(R)-P-Phos (R=H) (R)-Xyl-P-Phos (R=Me)

R

R

(R)-BINAP (R=H) (R)-TolBINAP (R=Me)

(R)-C1-C6-TunePhos (n=1-6)

CatASiumTM T1 (R=R'=H) CatASiumTM T2 (R=H, R'=Me) CatASiumTM T3 (R=Me, R'=H)

R

Fe

Ph

P NH

P N P R'

O NH P

P

P O P

O O

PPh2 PPh2 P Ph

MeBoPhoz (R=H, R'=Me) p-FPhMeBoPhoz (R=F, R'=Me) BnBoPhoz (R=H, R'=Bn)

(R)-H8-BINAMP

(R)-SpirOP

(R)-DiPh-MeO-Biphep

PhanePhos

The tests were performed on 0.2-0.3 mmol scale (depending on the requirements of the screening equipment used) in MeOH at a substrate concentration 0.1 mmol/ml, substrate to catalyst molar ratio (S/C) of 100/1, under 30 bar hydrogen pressure (60 bar in some experiments) at 60ºC for 18-20 hours.6,7 Conversion and enantioselectivity was determined by chiral HPLC for all substrates except compound 6 which co-eluted with (R)-enantiomer of the corresponding reduced carbamate. In this case, the conversion was assessed by 1H-NMR and the enantioselectivity was determined by chiral HPLC only when the reaction reached full conversion. As shown in Table 1, many ruthenium catalysts performed quite well under those conditions providing full conversion and e.e. values around 90%. The best results were obtained for substrates 3 and 5, with compound 6 being slightly less reactive and compound 7 significantly less reactive. Reactivity of a catalyst with a given substrate was mostly determined by the biphosphine ligand with little influence of a secondary ligand. The clear exception is acetylacetonate ligand which gave low activity catalysts with various biphosphines (e.g. entries 8, 9, 20, 33, 42, 43). Enantioselectivity of a catalyst also depended mainly on the structure of the biphosphine ligand with no clear trends for secondary ligands. Table 1. Initial screening of preformed isolated ruthenium catalystsa ACS Paragon Plus Environment

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Entry Catalyst

H2 Substrate pressure (bar)

1

RuCl2-(R)-P-Phos-(dmf)2

3

2

RuCl2-(R)-MeBoPhoz-(dmf)2

3

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Conversion (%)

Enantiomeric excess (%)

30

97

80 (R)

3

30

99

85 (R)

4

[RuCl(S)-P-Phos(benzene]Cl

3

30

97

79 (S)

5

[RuCl(R)-P-Phos(p-cymene)]Cl

3

30

54

83 (R)

6

[RuCl(R)-Xyl-P-Phos(p-cymene)]Cl

3

30

99

84 (R)

7

[RuCl(R)-TolBINAP(p-cymene)]Cl

3

30

99

92 (R)

8

Ru(R)-Xyl-P-Phos(acac)2

3

30

99

89 (S)

24

[RuCl(S)-C4-TunePhos]2(µ-Cl)3(Et2NH2)

3

60

>99

91 (S)

25

RuCl2-(R)-P-Phos-(dmf)2

5

30

98

79 (R)

26

RuCl2-(R)-Xyl-P-Phos-(dmf)2

5

30

>99

84 (R)


6

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27

[RuCl(S)-P-Phos(benzene]Cl

5

30

89

79 (S)

28

[RuCl(R)-P-Phos(p-cymene)]Cl

5

30

80

79 (R)

29


5

30

99

89 (R)

30


5

30

99

92 (R)

31


5

30

99

92 (R)

32

RuCl2-(R)-MeBoPhoz-(dmf)2

5

30

99b

80 (S)

37

[RuCl(S)-P-Phos(p-cymene)]Cl

6

30

41b

NDc

38

[RuCl(S)-P-Phos(benzene)]Cl

6

30

92b

NDc

39


6

30

73b

NDc

40


6

30

94b

NDc

41

[RuCl(S)-BINAP(p-cymene)]Cl

6

30

90b

NDc

42


6

30

99

93 (R)

9

[RuCl(R)-C3-TunePhos(p-cymene)]Cl

3

H3PO4

98

90 (R)

10

Ru(R)-C3-TunePhos(acac)2

3

H3PO4

>99

92 (R)

11


3

CF3COOH

>99

91 (R)

12


3

AcOH

98

90 (R)

13


6

H3PO4

>99b

86 (R)

14

[RuCl(R)-C3-TunePhos(p-cymene)]Cl

6

H3PO4

>99b

90 (R)

15

RuCl2-(S)-C3-TunePhos-(dmf)m

6

H3PO4

>99b

89 (S)

16


7

H3PO4

75

90 (R)

a

Reaction conditions: 0.1M substrate in MeOH, S/acid/C=100/25/1, unoptimised reaction time 18-20 h. Conversion and e. e. were determined using Diacel ChiralPak AD-H column at 210 nm, MeOH - 2propanol 7:3, 0.5 ml/min. bDetermined using 1H-NMR. c48% by-product. d52% by-product. The effect of acid was even more pronounced for non-isolated catalysts (Table 6).7,8 In the presence of phosphoric acid all pre-formed catalysts performed very well providing full conversion and improved enantioselectivity. The most striking difference was found for the catalyst formed from CatASiumTM T2 ligand according to procedure E (entry 5) – the same experiment without acid afforded only 8%


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conversion (Table 2, entry 8). In situ formed catalysts worked better with acid as well, achieving in the case of dichloro-(p-cymene)-ruthenium precursor practically full conversion (Table 6, entry 9). Table 6. Effect of phosphoric acid on the performance of non-isolated ruthenium catalystsa Entry

Biphosphine ligand or Ligand/Ru precursor

Preformation procedure

Substrate Conversion Enantiomeric (%) excess (%)

1

CatASiumTM T1

E

3

100

94 (R)

2

CatASiumTM T1

F

3

100

91 (R)

3

CatASiumTM T2

C

3

100

80 (R)

4

CatASiumTM T2

D

3

100

85 (R)

5

CatASiumTM T2

E

3

100

93 (R)

6

CatASiumTM T2

F

3

100

85 (R)

7

CatASiumTM T3

E

3

100

95 (R)

8

CatASiumTM T3

F

3

100

93 (R)

9b

(R)-C3-TunePhos/[Ru(p-cymene)Cl2]2

in situ

3

99

90 (R)

10b

(R)-C3-TunePhos/[Ru(benzene)Cl2]2

in situ

3

94

74 (R)

11b

(R)-C3TunePhos/Ru(COD)(methylallyl)2

in situ

3

81

69 (R)

a

Reaction conditions: 0.25M substrate in 10% (v/v) H3PO4 in MeOH, S/C=100, unoptimised reaction time 18-20 h. Conversion and e. e. were determined using Diacel ChiralPak AD-H column at 210 nm, MeOH - 2-propanol 7:3, 0.5 ml/min. b0.1M substrate in MeOH, S/acid/C=100/25/1. Effect of hydrogen pressure and temperature in Ru catalysed reduction Experiments at varying temperatures and pressures were performed in MeOH and showed that the activity to be both temperature dependent and pressure dependent at low temperatures as it was exemplified by Xyl-P-Phos based catalyst (Table 7, entries 1-4).6 Addition of phosphoric acid afforded further activation of the catalyst and allowed full conversion at low temperature (entry 5). Notably, the enantioselectivity of the reaction was neither temperature nor pressure dependent. As it was shown for C3- and C4-TunePhos ligands, the hydrogenation temperature could be increased up to 100ºC without detrimental effect on the performance of the catalysts. In the presence of acid, these catalysts


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demonstrated no effect of temperature on conversion and enantioselectivity in the range from 40ºC to 100ºC (entries 6-12).7 Table 7. Effect of temperature and hydrogen pressure on the performance of isolated ruthenium catalystsa Entry Catalyst

Substrate S/C/H3PO4

Temp. (ºC)

H2 (bar)

Conversion E. e. (%) (%)

1


5

100/1/-

30

30

99

90 (R)

5


5

100/1/25

30

30

>99

93 (R)

6


3

250/1/63

40

30

>99

92 (R)

7


3

250/1/63

60

30

>99

91 (R)

8


3

250/1/63

80

30

>99

91 (R)

9


3

250/1/63

100

30

>99

90 (R)

10

Ru(S)-C4-TunePhos(acac)2

3

250/1/63

40

30

>99

92 (S)

11


3

250/1/63

60

30

>99

92 (S)

12


3

250/1/63

80

30

>99

92 (S)

13


3

250/1/63

100

30

>99

91 (S)

a

Reaction conditions: 0.1M substrate in MeOH, unoptimised reaction time 18-20 h. Conversion and e. e. were determined using Diacel ChiralPak AD-H column at 210 nm, MeOH - 2-propanol 7:3, 0.5 ml/min. Results of temperature and pressure experiments with pre-formed non-isolated CatASiumTM series catalysts are given in Table 8. The study was performed at more demanding S/C ratio (500/1) using substrate 3.8 There were similar trends for CatASiumTM T1 and CatASiumTM T3 ligands although CatASiumTM T3 based catalyst was more active under other equal conditions, achieving full conversion even without acid (entry 16). Temperature appeared to be much more important parameter than the hydrogen pressure – it was possible to reach full conversion at high temperature and low pressure (entry 25) but not at low temperature and high pressure (entry 22). Enantioselectivity was not significantly ACS Paragon Plus Environment

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affected by either parameter. Beneficial effect of phosphoric acid at concentrations from 0.01% to 1% on conversion and enentioselectivity was confirmed for CatASiumTM based catalytic systems. Table 8. Effect of temperature and hydrogen pressure on the performance of non-isolated CatASiumTM catalystsa Entry Ligand

Acid

Temp (ºC)

H2 (bar)

Conversion (%)

E. e. (%)

1

CatASiumTM T1

no acid

60

30

0

2

CatASiumTM T1

no acid

60

70

2

3

CatASiumTM T1

no acid

80

30

0

4

CatASiumTM T1

no acid

80

70

72

5

CatASiumTM T1

0.01% H3PO4

60

30

0

6

CatASiumTM T1

0.01% H3PO4

60

70

30

89 (R)

7

CatASiumTM T1

0.01% H3PO4

80

30

38

89 (R)

8

CatASiumTM T1

0.01% H3PO4

80

70

100

91 (R)

9

CatASiumTM T1

0.1% H3PO4

60

30

12

87 (R)

10

CatASiumTM T1

0.1% H3PO4

60

70

46

91 (R)

11

CatASiumTM T1

0.1% H3PO4

80

30

100

92 (R)

12

CatASiumTM T1

0.1% H3PO4

80

70

100

91 (R)

13

CatASiumTM T3

no acid

60

30

0

14

CatASiumTM T3

no acid

60

70

5

62 (R)

15

CatASiumTM T3

no acid

80

30

26

88 (R)

16

CatASiumTM T3

no acid

80

70

100

89 (R)

17

CatASiumTM T3

0.01% H3PO4

60

30

18

86 (R)

18

CatASiumTM T3

0.01% H3PO4

60

70

52

92 (R)

19

CatASiumTM T3

0.01% H3PO4

80

30

91

93 (R)

20

CatASiumTM T3

0.01% H3PO4

80

70

100

92 (R)

21

CatASiumTM T3

0.1% H3PO4

60

30

37

79 (R)

22

CatASiumTM T3

0.1% H3PO4

60

70

73

94 (R)


57 (R)

87 (R)

16

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23

CatASiumTM T3

0.1% H3PO4

80

30

100

93 (R)

24

CatASiumTM T3

0.1% H3PO4

80

70

100

92 (R)

25

CatASiumTM T3

0.1% H3PO4

80

20

100

95 (R)

26

CatASiumTM T3

1% H3PO4

80

20

100

94 (R)

a

Reaction conditions: 0.33M substrate in MeOH, S/C=500, unoptimised reaction time 18-20 h. Procedure E used for the catalyst formation. Conversion and e. e. were determined using Diacel ChiralPak AD-H column at 210 nm, MeOH - 2-propanol 7:3, 0.5 ml/min. Optimisation and scale-up of reaction with pre-formed non-isolated CatASiumTM T3 catalyst8 Only substrate 3 (up to 3 g scale) was used for this study. Different S/C ratios (1000, 2000, 4000) were tested with CatASiumTM T3 at 30 bar and 80°C in the presence of 0.1% H3PO4 (Table 9). Two ways for increasing the S/C ratio were applied: by keeping constant the amount of substrate (maintaining constant the concentration at the same values as in the experiments at S/C 500, Table 8) and lowering the amount of catalyst (Table 9, entries 3 and 5); and by keeping constant the amount of catalyst and increasing the amount of substrate (Table 9, entries 4 and 6). Full conversion was achieved only at S/C 1000/1. Already at S/C 2000/1 the reactivity was low, especially at higher substrate concentration (entries 3-4). There was no attempt to use higher acid concentration at lower catalyst loading as this was detrimental for the conversion at S/C 1000/1 (entry 2). Table 9. Optimisation of pre-formed non-isolated CatASiumTM T3 catalysta Entry

S/C

H3PO4 (%)

[S] (mmol/ml)

Conversion (%)

E. e. (%)

1

1000

0.1

0.33

100

92 (R)

2

1000

1

0.33

75

74 (R)

3

2000

0.1

0.33

19

84 (R)

4

2000

0.1

0.66

0

NDb

5

4000

0.1

0.33

3

76 (R)

6

4000

0.1

1.33

5

2 (R)

a

Reaction conditions: substrate in MeOH, 30 bar H2, 80ºC, unoptimised reaction time 18-20 h. Conversion and e. e. were determined using Diacel ChiralPak AD-H column at 210 nm, MeOH - 2propanol 7:3, 0.5 ml/min. bND – not determined.


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The scale-up experiment was carried out with 800 g of substrate 3 in a 15 L autoclave under the following conditions: catalyst CatASiumTMT3/[Ru(p-cymene)Cl2]2 in EtOH/CH2Cl2, hydrogen pressure 20 bar, temperature 80°C, S/C 2000/1, concentration 0.7 M, additive 0.1 % H3PO4. The experimental procedure was as follows: [Ru(p-cymene)Cl2]2 and CatASiumTM T3 were stirred at 50°C for 90 minutes in a mixture of dichloromethane/EtOH (1:1) and then cooled to room temperature. The 15 L autoclave was charged with the substrate, methanol and the corresponding additive under argon atmosphere. Afterwards the catalyst was added. The reaction was hydrogenated for 18 hours at the conditions given above (conversion >99%, 95% e.e. by HPLC). Deloxan® was added to the reaction mixture and the catalystadsorbed resin was separated by filtration. During the evaporation of the solvent (approx. 2000 ml out of 6000 ml) a formation of a precipitation occurred. The distillation was stopped at approx. 5000 ml of distillate and the precipitation was filtered off and washed with a small amount of methanol. The isolated solid (white crystals) was dried under vacuum (180-210 mbar) at 40°C for 18 hours to give compound 4 (730.43 g, 90.55% yield, >99% e.e.). The reason for better result of the scale-up experiment compared to the optimisation runs with the same catalyst loading (Table 9, entries 3-4) remained unclear. As the same batches of substrate, ligand and Ru precursor were used for all experiments, the lower conversion on small scale might be attributed to a scale effect (volume to surface ratio, stirring efficiency etc.). Optimisation and scale-up of reaction with pre-formed non-isolated (R)-TolBINAP catalyst9 Isolated


catalyst

displayed

very

good

conversion

and

enantioselectivity in the screening experiment (Table 1, entry 7). Several pre-formed non-isolated (R)TolBINAP catalysts were tested at more demanding S/C ratio of 1000/1 at 30 bar hydrogen pressure and 80ºC (Table 10). The experiments with (R)-TolBINAP/[Ru(C6H6)Cl2]2 and (R)-TolBINAP/[Ru(pcymene)Cl2]2 catalysts (pre-formed in EtOH-DCM) in the presence of 0.1% H3PO4 gave the best results (entries 4-5). The entry 5 combination with more available [Ru(p-cymene)Cl2]2 precursor was used for the further development. ACS Paragon Plus Environment

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Table 10. Optimisation of pre-formed non-isolated (R)-TolBINAP catalysta Entry Ru precursor

Pre-formation procedure

H3PO4 (%)

Conversion (%)

E. e. (%)

1

[Ru(C6H6)Cl2]2

C

no acid

75

88 (R)

2

[Ru(C6H6)Cl2]2

C

0.1

94

89 (R)

3

[Ru(C6H6)Cl2]2

D

no acid

89

89 (R)

4

[Ru(C6H6)Cl2]2

D

0.1

100

90 (R)

5

[Ru(p-cymene)Cl2]2

D

0.1

100

89 (R)

6

Ru(COD)(methylallyl)2

F

no acid

98

90 (R)

7

Ru(COD)(methylallyl)2

F

0.1

97

90 (R)

a

Reaction conditions: 0.25M substrate in MeOH, S/C=1000, 30 bar H2, 80ºC, unoptimised reaction time 18-20 h. Conversion and e. e. were determined using Diacel ChiralPak AD-H column at 210 nm, MeOH - 2-propanol 7:3, 0.5 ml/min. To study the scalability of the process, experiments with 6 g and 24 g of the substrate 3 were performed, both giving complete conversion with 90% and 91% e.e. respectively. For further process development the reagent grade methanol from the shelf was used and degassed by distilling off 10% of the solvent volume from the autoclave. The experiment was successful on 12 g scale, which was then repeated at 24 g and 50 g scale with a simultaneous increase of the substrate concentration from 0.25M to 0.5M. Further gradual decrease of the catalyst loading was quite successful as well, achieving 99% conversion at S/C ratio of 2000/1 (Table 11, entry 3). The intermediate scale-up experiments with (R)-TolBINAP/[Ru(p-cymene)Cl2]2 catalyst were also used for development of the isolation procedure for the reduced carbamate 4 with simultaneous upgrade of enantiomeric purity. Crystallisation of compound 4 upon concentration of the methanolic solution to 1.25 volumes after CatASiumTMT3/[Ru(p-cymene)Cl2]2 catalysed reduction was taken as a starting point for the development. Although the procedure afforded pure compound in high yield, obviously the solubility of 4 in methanol was too high and another alcohol or an alcohol-water mixture was required for a comfortable and reproducible operation. Screening of various solvent systems revealed a 2propanol-water mixture (45:55 v/v) to have acceptable combination of purging capability towards ACS Paragon Plus Environment

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Page 20 of 25

unwanted enantiomer and yield of the wanted one. The product from the hydrogenation reaction was recrystallised in the above mixture to produce an almost optically pure product (99.6-99.8% e.e.) in 8889% overall yield. Some representative results are given in Table 11. Enantiomeric excess of the liquors from experiments in Table 11 was close to 24%. Table 11. Scale-up experiments with non-isolated (R)-TolBINAP/[Ru(p-cymene)Cl2]2 catalysta Entry

Substrate 3 (g)

S/C

Conversion (%)

Reaction e. e. (%)

mixture Isolated yield Product e. e. (g (%)) (%)

1

50

1000

100

90.9

44.2 (88)

99.7

2

50

1800

99.6

91.0

44.5 (88)

99.7

3

40

2000

99.3

90.6

35.8 (89)

99.7

a

Reaction conditions: 0.5M substrate in MeOH, 30 bar H2, 80ºC, unoptimised reaction time 18-20 h. Conversion and e. e. were determined using Diacel ChiralPak AD-H column at 210 nm, MeOH - 2propanol 7:3, 0.5 ml/min. The experimental procedure was as follows: (R)-TolBINAP (0.152 g, 0.224 mmol) and dichloro(p-cymene)ruthenium(II) dimer (0.063 g, 0.104 mmol) were stirred in a Schlenk type apparatus (25 mL) in a mixture of ethanol (anhydrous, degassed by Ar bubbling for 0.5 h) (8 ml) and DCM (anhydrous, degassed by Ar bubbling for 0.5 h) (4 ml) at 45ºC (slow reflux) under Ar for 1.5 h, cooled to room temperature; the solution was used directly for hydrogenation. The substrate 3 (50 g, 207 mmol) and MeOH (400 ml, reagent grade) were charged in a 500 mL stainless steel autoclave, the autoclave was sealed and 40 ml of methanol was distilled off via the outlet tube with magnetic stirring. The outlet was closed without removal of the heating at 65ºC, the hydrogen pressure (7 bar) was applied and the solution was allowed to cool down to 25ºC with stirring. 1% (w/w) H3PO4 in MeOH (40 ml, prepared from 85% aq H3PO4) was added via syringe with slow stream of hydrogen. The solution was degassed 5 times by applying and releasing the hydrogen pressure (20 bar) with stirring at 20-25ºC and the catalyst solution was added via syringe with a slow stream of hydrogen. The autoclave was closed, charged with hydrogen (30 bar) and heated at 80ºC (internal, thermocouple) with magnetic stirring for 20 h. The pressure was released after cooling to 20-25ºC, 0,025 mL of the 20 ACS Paragon Plus Environment

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solution was diluted to 10 mL, and the reaction was monitored for disappearance of 3 and e.e. measurement directly by chiral HPLC. The solution was evaporated to dryness under reduced pressure, the residue was dissolved in the mixture of 2-propanol and water (45:55 v/v, 335 ml) with stirring under reflux, the solution was cooled with water to approx. 30ºC (crystallisation occured at 45ºC) with stirring, then with ice to 5ºC and stirred for 1 h at 5ºC. The precipitate was collected on a sintered glass filter No. 2 (slow filtration occurred when filter paper was used), washed with the mixture of 2-propanol and water (45:55 v/v, 2025ºC, approx. 75 ml), dried in vacuum at 50ºC to constant weight to give compound 4 (44.2 g, 88 % yield). Reaction conditions optimisation for isolated Ru(R)-Xyl-P-Phos(acac)2 catalyst6 Optimisation of asymmetric hydrogenation conditions using isolated Ru(R)-Xyl-P-Phos(acac)2 catalyst was performed using up to 1.5 mmol of substrate at 30 bar hydrogen pressure and 60-70ºC in the presence of phosphoric acid, increasing the concentration of the substrate and keeping constant substrate to acid ratio (Table 12). Under those conditions substrate 3 was marginally more reactive, allowing the substrate to catalyst ratio as low as 1000/1 to be used. At this low catalyst loading the enantioselectivity was slightly reduced (entries 4-5) if compared to S/C ratio of 100/1 (Table 5, entries 7-8). Reaction mixtures of substrate 3 that reached >98% conversion and >90% e.e. were combined, and tested for enantiopurity upgrade via recrystallisation. From one recrystallisation experiment, it was found that from DCM/hexane, the enantiopurity of product 4 could be upgraded from 91% e.e. to 98.7% e.e. with 70% yield. Table 12. Optimisation of isolated Ru(R)-Xyl-P-Phos(acac)2 catalysta Entry

Substrate

S/C

H3PO4/C

Temp (ºC)

[S] (mmol/ml) Conversion (%)

E. e. (%)

1

3

250

63/1

60

0.1

>99

92 (R)

2

3

500

125/1

60

0.2

>99

89 (R)

3

3

750

190/1

60

0.33

>99

90 (R)

4

3

1000

250/1

60

0.5

>99

90 (R)


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Page 22 of 25

5

3

1000

250/1

70

0.5

>99

90 (R)

6

5

750

190/1

60

0.33

95

89 (R)

7

5

1000

250/1

60

0.5

>99

90 (R)

8

5

1000

250/1

70

0.5

98

89 (R)

a

Reaction conditions: substrate in MeOH, 30 bar H2, unoptimised reaction time 18-20 h. Conversion and e. e. were determined using Diacel ChiralPak AD-H column at 210 nm, MeOH - 2-propanol 7:3, 0.5 ml/min. Optimisation and scale-up of reaction with isolated Ru(R)-C3-TunePhos(acac)2 catalyst7 Optimisation of asymmetric hydrogenation conditions using substrate 3 and isolated Ru(R)-C3TunePhos(acac)2 catalyst was performed at 30 bar hydrogen pressure and 80ºC in the presence of phosphoric acid, keeping constant substrate to acid ratio (Table 13). Full conversion was achieved at S/C ratio of 3000/1 (entry 2), however at S/C 4000/1 the main part of the substrate (83%) was reduced as well (entry 3), without loss of enantioselectivity. Table 13. Optimisation of isolated Ru(R)-C3-TunePhos(acac)2 catalysta Entry

S/C

H3PO4/C

[S] (mmol/ml)

Conversion (%)

E. e. (%)

1

2000

500/1

0.33

>99

90 (R)

2

3000

750/1

0.5

>99

89 (R)

3

4000

1000/1

0.5

83

89 (R)

a

Reaction conditions: substrate in MeOH, 30 bar H2, 80ºC, unoptimised reaction time 18-20 h. Conversion and e. e. were determined using Diacel ChiralPak AD-H column at 210 nm, MeOH - 2propanol 7:3, 0.5 ml/min. Two scale-up experiments were carried out on 1 kg and 5 kg scale with S/C ratio 4000/1 and 3000/1 respectively (Table 14). Table 14. Scale-up experiments with isolated Ru(R)-C3-TunePhos(acac)2 catalyst Entry Substrate 3 Catalyst (g) (g)

85%H3PO4 MeOH Reaction Isolated yield Product e. e. (g) mixture e. e. (g (%)) (%) (L) (%)

1

950

0.894

113

5

92

861 (90)

99.9

2

5000

6.28

600

20

91

4456 (88)

>99


22

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Both experiments were performed at 80-85ºC and 30-35 bar of hydrogen pressure, and reached full conversion within 24 h. The general procedure for the 5 kg scale experiment was as follows: Methanol (20 L) was charged to the autoclave (stainless steel, T36) followed by the substrate and 85% H3PO4. The autoclave was purged with nitrogen to replace the air inside, then the ruthenium catalyst was charged to the autoclave under nitrogen atmosphere. The reactor was sealed and nitrogen replaced with hydrogen (30 bar). The reaction mixture was heated with stirring to 80ºC and held at 80-85ºC for 24 hours while maintaining the hydrogen pressure at 30-35 bars. Then the mixture was cooled to 2530ºC and the conversion checked (~ 100%). The hydrogen pressure was released and the autoclave purged with nitrogen. The resulting suspension was transferred to the rotavap and concentrated to dryness under reduced pressure. The crude product was dissolved in the mixture of isopropanol and water (45:55, v/v, 33.3 L) with stirring under reflux. The clear solution was cooled to room temperature and further cooled to 0-5ºC and kept at 0-5ºC for 1 hour. The precipitate was collected by filtration and washed with the mixture of isopropanol and water (45:55, v/v, 7.5 L). The product was dried at 50ºC in vacuum to constant weight. Conclusion The screening program allowed to identify four ruthenium based catalytic systems for asymmetric hydrogenation of pro-chiral ene carbamate 3: two isolated catalysts Ru(R)-Xyl-P-Phos(acac)2 and Ru(R)-C3-TunePhos(acac)2; and two pre-formed non-isolated catalytic systems CatASiumTMT3/[Ru(pcymene)Cl2]2 and (R)-TolBINAP/[Ru(p-cymene)Cl2]2. The processes were successfully optimized as regards the catalyst loading - Ru(R)-C3-TunePhos(acac)2 system up to S/C ratio 4000/1 and both systems with non-isolated catalysts up to S/C 2000/1. Scalability was demonstrated at 5 kg scale for Ru(R)-C3-TunePhos(acac)2 and 1 kg for CatASiumTMT3/[Ru(p-cymene)Cl2]2. Both isolated and non-isolated catalysts have their own merits, and both methods are used almost equally on industrial scale.11 The most evident advantage of the isolated ones is lower catalyst loading – for unclear reasons pre-formation of the catalyst in solution in most cases produces less reactive species. However, this well may be the only advantage. Typically, isolated catalysts are less stable and more ACS Paragon Plus Environment

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oxygen and moisture sensitive than the corresponding ligand and metal precursor, which creates additional difficulties for storage and handling of the material on scale. Analysis and release of the catalyst may be challenging as well. In some cases, in order to ensure the catalyst to be working at required low loading, a use-test is performed even if the product meets specifications. Last but not least is the cost of isolated catalyst which tends to be much higher than the cost of its components. In terms of commercial efficacy, using low loading of isolated catalyst may be as convenient as larger amount of non-isolated one. Selection of the catalytic system for asymmetric hydrogenation of ene carbamate 3 on industrial scale will be made based on the ease of use, cost and availability of catalyst or biphosphine ligand and ruthenium precursor. References (1) Beliaev, A.; Learmonth, D.A.; Soares-da-Silva, P. Synthesis and biological evaluation of novel, peripherally selective chromanyl imidazolethione-based inhibitors of dopamine β-hydroxylase. J. Med. Chem. 2006, 49, 1191. (2) Almeida, L.; Nunes, T.; Costa, R.; Rocha, J. F.; Vaz-da-Silva, M.; Soares-da-Silva, P. Etamicastat, a novel dopamine β-hydroxylase inhibitor: tolerability, pharmacokinetics, and pharmacodynamics in patients with hypertension. Clin. Ther. 2013, 35, 1983, doi: 10.1016/j.clinthera.2013.10.012. (3) Beliaev, A.; Wahnon, J.; Russo, D. Process Research for Multikilogram Production of Etamicastat: A Novel Dopamine β-Hydroxylase Inhibitor. Org. Process Res. Dev. 2012, 16, 704. (4) Dupau, P.; Bruneau, C.; Dixneuf, P. H. New route to optically active amine derivatives: ruthenium catalyzed enantioselective hydrogenation of ene carbamates. Tetrahedron: Asymmetry 1999, 10, 3467. (5) Dupau, P.; Hay, A.-E.; Bruneau, C.; Dixneuf, P. H. Synthesis of optically active 2-aminotetraline derivatives

via enantioselective ruthenium-catalyzed

hydrogenation of ene carbamates

Tetrahedron: Asymmetry 2001, 12, 863. ACS Paragon Plus Environment

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(6) Learmonth, D. A.; Zanotti-Gerosa, A.; Grasa, G. A.; Beliaev, A. Process. PCT Int. Appl. WO2008071951A2, 19 Jun 2008. (7) Beliaev, A.; Learmonth, D. A.; Li, W. Process. PCT Int. Appl. WO2009116883A2, 24 Sep 2009. (8) Beliaev, A.; Learmonth, D. A.; Almena Perea, J. J.; Geiß, G.; Hitzel, P.; Kadyrov, R. Catalytic process for asymmetric hydrogenation. PCT Int. Appl. WO2009113891A1, 17 Sep 2009. (9) Beliaev, A.; Learmonth, D. A. Process. PCT Int. Appl. WO2009136803A2, 12 Nov 2009. (10) Ernst, R. D.; Melendez, E.; Stahl, L.; Ziegler, M. L. cis-and trans-Diene coordination in ruthenium (II) acetylacetonate compounds. Organometallics 1991, 10, 3635-3642. (11) Farina, V.; Reeves, J. T.; Senanayake, C. H.; Song, J. J. Asymmetric Synthesis of Active Pharmaceutical Ingredients. Chem. Rev. 2006, 106, 2734-2793.


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Development of the Asymmetric Hydrogenation Step for Multikilogram

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