Optical resolution trials and a process-concept assessment of the industrial scale-up

Optical resolution trials and a Optical resolution trials and a process-concept assessment process-concept assessment of the industrial scale-upof the industrial scale-up

PhD dissertation

Compiled by: Katalin NemákSupervised by: Dr. István Hermecz

CHINOIN Zrt. BME

2

Katalin Nemák Presentation of PhD theses May 28. 2009

Topic of the dissertation Topic of the dissertation

In my work for the PhD degree I dealt with the synthesis and the optical resolution of pipecolo-anilides.

The goal of my work was to elaborate robust procedures for the production of the pure enantiomers of the known local

anesthetic pipecolicolo-xylidides and to investigate the resolution process in details for rendering it more

predictable.

Based on the experiences of the lab trials I conducted a trial production and I draw up planes for the validation of the

manufacturing and the resolution of the mentioned substances in industrial scale.

3


R1 R2 R3 R4 Group

1. H CH3 CH3 H

* 2. Me CH3 CH3 H

3. Et CH3 CH3 H

**4. n-Pr CH3 CH3 H ***5. n-Bu CH3 CH3 H

Pipecolo- xylidides

6. H H H H

7. Et H H H

8. n-Pr H H H

9. n-Bu H H H

Pipecolo- anillides

10. H H H CF3

11. Et H H CF3

12. n-Pr H H CF3

13. n-Bu H H CF3

Pipecolo-trifluoromethyl-

anilides

13 13 NN-alkyl-pipecolo-anilid derivatives were -alkyl-pipecolo-anilid derivatives were synthesized (1-13) synthesized (1-13)

1

7 new compounds

Known local anesthetics:: *2 – mepivacaine, **4 – ropivacaine, ***5 – bupivacaine

N

O

NH

R

R

R

R1

2

3

4

4


Preparation of the model-substances Preparation of the model-substances in 3 synthetic stepsin 3 synthetic steps

A. Condensation: Acylation of aniline derivatives by picolinic acid. (Y=82- 87%)

B. Catalytic hydrogenation: Transformation of picolinic acid anilides to pipecolo-anilides. (Y=89- 94%)

C. N-Alkylation: Reaction of the pipecolo-anilides with alkyl-halogenides. (Y=63- 90%)

NH2

R

R3

2

R4

N

O

OHN

O

NH

R

R

R

3

2

4

+POCl3

savmegkötõ

NH

O

NH

R

R

R

3

2

4

N

O

NH

R

R

R

3

2

4

H2, 10% Pd/C

MeOH

1

[4]

N

O

NH

R

R

R

R

NH

O

NH

R

R

R

+ R1Br

KI, K2CO3

MiBK

2

3

4

1

2

3

4

5


All 13 model-substances were resolved to All 13 model-substances were resolved to their optical isomers their optical isomers

Resolvingacid/solv.

DBTA,IPA

DBTA,EtOH

DBTA,IPA

TA,EtOH

TA,IPA

[1,2,3]

1

Resolution processes of the Resolution processes of the NN-alkyl-pipecolo-xylidides were investigated in details,-alkyl-pipecolo-xylidides were investigated in details,the enantiomers were produced in high purity.the enantiomers were produced in high purity.

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Detailed investigation of the resolution Detailed investigation of the resolution procedureprocedure

crystallinephase

Diastereomer formation

Selectíve crystallisation

Recrystallisation

Breaking thediastereomermother

liquor

Recrystallisation

Breaking thediastereomer

Following the steps backward from the end

(practice adopted from investigation using FMEA)

PROCESS FLOW

INVESTIGATION FLOW

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[1]

2

Racemates

Conglomerate

Based on the direction of the curves it can be predicted whether the crystalline phase or the mother liquor will contain the recrystallised enantiomer-mixture with higher purity

Application of biner phase-diagrams during Application of biner phase-diagrams during purification - recrystallizationpurification - recrystallization

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’S’ = 0,517 · π + 2,280 · σ* – 0,015 · ET – 0,001

Relationship between the chromatographic retentions Relationship between the chromatographic retentions ((ΔRf) and the efficiency of resolution (‘S’) ) and the efficiency of resolution (‘S’)

[2]

standardized

3

Tetrahedron Letters 21, 647-50 (1980) Golumbić-rule

Chromatographic checking of salt formation: spots of the racemic mixtures of the diastereomeric salts composed from N-alkyl-pipecolo-xylidides and DBTA together with the constituents (TLC-s were

developed in the laboratory using the butanol-glacial acetic acid-water 60:15:25 eluent.)

DBTA

Pipecolo-xylidides

(1) (2) (3) (4) (5)

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Statistical verification of the correlationStatistical verification of the correlation

D1 data set - Line Plot (PhD-data_June_2008.sta 10v*14c)

deltaRf_D1 'S' DBTA_D10.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

unit:

val

ue*1

00 =

%

Case 1 Case 2 Case 3 Case 4 Case 5 Case 6 Case 7 Case 8 Case 9 Case 10 Case 11 Case 12 Case 13 Case 14

Scorr=0,785

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Resolution of Resolution of N-N-alkyl-pipecolo-anilides and alkyl-pipecolo-anilides and –trifluoromethyl-anilides –trifluoromethyl-anilides

With tartaric acid (TA) or Dibenzoyl-tartaric acid (DBTA)

A new method for the design of resolutions was suggested. Based on the TLC results I designed the trial resolutions which

gave good results even for the first couple of attempts.

Successful trials: at the first attempt – 1, at the second - 2

3

[2]

R1 Sol-vent

ΔRf* Yeald %/ no of trial

E.P.

% [α]D

20 R1 Sol-vent

ΔRf* Yeald %/ no of trial

E.P.

%

[α]D20

R2 = R3 = H, R4 = H, Pipecolo-anilides (6-9)

H (6) EtOHaq 0,570 67,5/1 10,0 +1,5 Et (7) i-PrOH 0,133 50,0/1 95 -120,4

Bu (9) EtOHaq 0,563 54,8/2 ? -26,0 Pr (8) i-PrOH 0,097 42,0/1 77 -102,6

R2 = R3 = H, R4 = CF3 Pipecolo-trifluoromethyl-anilides (10-13)

H (10) EtOH 0,587 65,2/2 15,0 +1,7 Et (11) i-PrOH 0,147 66,8/1 91,4 -56,6

Bu (13) EtOH 0,594 58,5/2 71,8 -64,0 Pr (12) EtOHaq 0,113 41,6/1 80,0 -62,4

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Temperature dependence of resolutionTemperature dependence of resolution

EE

Temperature optimum of the resolution for racemates was found between 45-55°C and for the conglomerate between 0-10°C.

4[3]

12


5

[4]

NH+

νasCOO-

νs COO-

Structure elucidation of theStructure elucidation of the diastereomersdiastereomers- Salt or cocrystal? - Salt or cocrystal?

Left: IR-spectrum of [N-etyl-pipecolo-xylidide]2 - DBT, with signals at 2719 cm-1 t-ammonium NH+, 1626 νas COO-, 1371 νs COO-

Underneath: IR-spectrum of mepivacaine – DBHT, without the signals mentioned above

Upper right: IR– spectrum of mepivacaine – HCl –with the signal of the protonated t-ammonium NH+ at 2503 cm-1

8 compounds out of the 13 had 1:1 acid : base molar ratio – none of them showed signals of the ionized acid and base components

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1

Supramolecular investigations I.Supramolecular investigations I.

2

3

4

The hydrogen-bonds between the tartrate parts found to be stronger than the ones connecting the mepivacaine.

1

2

3

4

6

[5]

Hydrogen-bridge bonds in the crystal structure of the precipitated

S(-)-mepivacaine-O,O’-2R,3R-dibenzoyl-hydrogentartrate

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Supramolecular investigations II.Supramolecular investigations II.

From the Cambridge Structure Database 84 DBTA –containing structures were selected and arranged in three groups: acidic salts, neutral salts and cocrystals. The 1:1 assembly we investigated proved to be an acidic salt.

In the DBTA–containing acidic salts the O…H...O type interactions found to be the strongest bonds. These were usually the head-to-tail bonds connecting the tartrate-chains.

During the crystal growth the preferential building up of the chiral bitartrate-chains gave a pillar structure which can capture only one of the enantiomers, and this way these structures can be used in separation procedures with high efficiency.

Crystallographic evaluation of the data of DBTA containing structures:

6

[5]

15


Process-concept approach in the evaluation Process-concept approach in the evaluation of the industrial scale-upof the industrial scale-up

7

[6]

ICH Q8: „Design Space”

Critical process parametersFor the estimation of the acceptable ranges of the technical set up parameters

I used the known equations of process engineering.

Product quality features - I used the technique of risk-analysis for the design of in-process controls to determine what to measure in which steps of the procedure.

Determination of critical operations with risk evaluation based on stringent analysis of each process steps of the flow-chart

Risky,Specific,Product contact

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Theses - achievementsTheses - achievements

1.Production of 13 pipecolo-anilides – 7 of them original new molecules.

2.Successful resolution of the racemic compounds - for all the 13.

3.Production of the pure enantiomers of the pipecolo-xylidides, evaluation of the purification methods and the behavior of the enantiomer-mixtures during purification was done based on the binary phase-diagrams.

4.Elaboration of a new method for the selection of the resolving agent and the solvent for the resolution based on the differences of the chromatographic retentions measured by TLC methods.

5.Optimization of the purification of the diastereomers with regards to the temperature dependence of the crystallization.

6.Characterization of the separated crystalline diastereomers by spectroscopic and supramolecular methods.

7.Conducting successful trial production of mepivacaine and planning of the production of the pure enantiomers in industrial scale based on the experiences in scaling up.

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PublicationsPublications

[1] Nemák, K., Ács, M., Kozma, D., Fogassy, E.: Racemic compound formation-conglomerate formation Part 4.: Optical resolution and determination of the melting phase diagrams of 2’,6’-pipecoloxylidide and four 1-alkyl- 2’,6’-pipecoloxylidides J. Thermal Anal. Vol. 48, pp.691-696 (1997)

[2] Nemák, K., Fogassy, E., Bényei, A., Hermecz, I.,: The Role of TLC in Investigation of Diastereomeric Salt formation by a Gruop of Pipecoloxylidides, Journal of Planar Chromatography 21(2), 125-128 (2008), DOI: 10.1556/JPC.21.2008.2.9,

[3] Nemák, K., Kozma, D., Fogassy, E.: Study of the mechanism of optical resolutions via diastereomeric salt formation. Part 4. The role of the crystallization temperature in optical resolution of pipecolic acid xylididesMol. Cryst. Liquid Cryst. 276, 31-36 (1996)

[4] Nemák, K., Ács, M., Jászay, M., Zs., Kozma, D, Fogassy, E.: Study of tthe Diastereisomers formed between (N-alkyl)-pipecolic acid-anilides and 2R,3R-tartaric acid. Do the Tartaric Acid Form molecular-Complexes, instead of Salts during Optical resolutions? Tetrahedron Vol. 52, No. 5, pp.1637-1642 (1996),

[5] Nemák, K., Bényei, A., Halász, J., Simon K. and Hermecz, I.,: Optical Resolution of Mepivacaine and Supramolecular Characterization of the Less Soluble Diastereomer – cikktervezet véleményezés alatt – Journal of Pharmaceutical and Biomedical Analysis

[6] Nemák, K., Vajdai, M., Kiss, T., Halász, J., Hermecz, I.,: Adapting to New Regulatory Requirements: FDA’s Risk-Based Approach to Compliance - How Industry Can Comply with New Concepts in Quality Management, - Közlésre elfogadva:American Pharmaceutical Outsourcing

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Optical resolution trials and a process-concept assessment of the industrial scale-up