tert-Butyl N-[(3R,4R)-1-(2-cyano­acet­yl)-4-methyl­piperidin-3-yl]-N-methyl­carbamate

Gehringer, M.; Forster, M.; Schollmeyer, D.; Laufer, S.

doi:10.1107/S1600536813013512

organic compounds

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ISSN: 2056-9890

Volume 69| Part 6| June 2013| Page o935

doi:10.1107/S1600536813013512

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tert-Butyl N-[(3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl]-N-methylcarbamate

Matthias Gehringer,^a Michael Forster,^a Dieter Schollmeyer ^b and Stefan Laufer ^a ^*

^aEberhard-Karls-University Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany, and ^bUniversity Mainz, Institut of Organic Chemistry, Duesbergweg 10-14, 55099 Mainz, Germany
^*Correspondence e-mail: stefan.laufer@uni-tuebingen.de

(Received 8 May 2013; accepted 16 May 2013; online 22 May 2013)

The piperidine ring of the title compound, C₁₅H₂₅N₃O₃, adopts a slightly distorted chair conformation with the cis substituents displaying an N—C—C—C torsion angle of 43.0 (3)°. The cyano group (plane defined by C—C—C≡N atoms) is bent slightly out of the plane of the amide group by 13.3 (2)°. The carbamate group is oriented at a dihedral angle of 60.3 (5)° relative to the amide group.

Related literature

For the biological activity and structure–activity relationships of Tofacitinib {systematic name: 3-[(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl]-3-oxopropanenitrile} derivatives, see: Changelian et al. (2003 ); Flanagan et al. (2010 ); Zerbini & Lomonte (2012 ). For details of the synthesis, see: Babu et al. (2010 ).

Experimental

Crystal data

C₁₅H₂₅N₃O₃
M_r = 295.38
Monoclinic, P 2₁
a = 7.1786 (11) Å
b = 7.3213 (10) Å
c = 16.042 (2) Å
β = 102.196 (4)°
V = 824.1 (2) Å³
Z = 2
Mo Kα radiation
μ = 0.08 mm⁻¹
T = 173 K
0.60 × 0.35 × 0.10 mm

Data collection

Bruker SMART APEXII diffractometer
5061 measured reflections
2115 independent reflections
1818 reflections with I > 2σ(I)
R_int = 0.031

Refinement

R[F² > 2σ(F²)] = 0.038
wR(F²) = 0.101
S = 1.03
2115 reflections
195 parameters
1 restraint
H-atom parameters constrained
Δρ_max = 0.24 e Å⁻³
Δρ_min = −0.17 e Å⁻³

Data collection: APEX2 (Bruker, 2006 ); cell refinement: SAINT (Bruker, 2006); data reduction: SAINT; program(s) used to solve structure: SIR97 (Altomare et al., 1999 ); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ); molecular graphics: PLATON (Spek, 2009 ); software used to prepare material for publication: PLATON.

Supporting information

Crystal structure: contains datablocks I, global. DOI: 10.1107/S1600536813013512/nc2311sup1.cif

Structure factors: contains datablock I. DOI: 10.1107/S1600536813013512/nc2311Isup2.hkl

Supporting information file. DOI: 10.1107/S1600536813013512/nc2311Isup3.cml

checkCIF report

Comment top

Tofacitinib (CP690,550) is a potent and selective Janus Kinase (JAK) 1/3 inhibitor (Changelian et al. (2003) and Flanagan et al., (2010)) which has recently been approved by the US Food and Drug Administration for the treament of rheumatoid athritis. Furthermore, it is currently in late stage clinical trials for treatment of psoriasis, inflammatory bowel disease, transplant rejection and other immunological disorders (Zerbini & Lomonte, (2012)). Searching for novel JAK inhibitors, the title compound was synthesized as a key intermediate possessing the Boc-protected Tofacitinib side chain.

In the crystal structure of the title compound the piperidine ring adopts a slightly distorted chair conformation with a torsion angle between the cis substituents of 43.0 (3)°. The carbamate group shows a dihedral angle of 60.3 (5)° relative to the amide group. The plane defined by atoms C17, C19, C20 and N21 is slightly bent out of the plane of the amide group by 13.3 (2)°.

Related literature top

For the biological activity and structure–activity relationships of Tofacitinib {systematic name: 3-[(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl]-3-oxopropanenitrile} derivatives, see: Changelian et al. (2003); Flanagan et al. (2010); Zerbini & Lomonte (2012). For details of the synthesis, see: Babu et al. (2010).

Experimental top

The title compound was prepared by cyanoacetylation of a precursor possessing a free piperidine NH-function (Babu et al., (2010)) using dicyclohexylcarbodiimide (DCC) and cyanoacetic acid.

tert-Butyl-N-methyl-N-[(3R,4R)-4-methylpiperidin-3-yl]carbamate (2.80 g, 12.3 mmol) was dissolved in 25 ml of dry methylen chloride and stirred under argon atmosphere. Cyano acetic acid (0.82 g, 9.64 mmol) and N,N'-dicyclohexylcarbodiimide (1.99 g, 9.64 mmol) was added in one portion while cooling with ice. After 15 min at 273 K, the ice bath was removed, the mixture warmed to room temperature (298 K) and stirring was continued for 3 h. N,N'-dicyclohexylurea was removed by filtration, washed with methylen chloride and the filtrate concentrated under reduced pressure. Purification by column chromatography (SiO₂, methylen chloride/ethyl acetate: 7 + 3) yielded the title compound as colorless solid (2.18 g, 84.3%). Crystals of the title compound were obtained by slow evaporation of methanol at room temperature (298 K).

Structure description top

For the biological activity and structure–activity relationships of Tofacitinib {systematic name: 3-[(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl]-3-oxopropanenitrile} derivatives, see: Changelian et al. (2003); Flanagan et al. (2010); Zerbini & Lomonte (2012). For details of the synthesis, see: Babu et al. (2010).

Computing details top

Data collection: APEX2 (Bruker, 2006); cell refinement: SAINT (Bruker, 2006); data reduction: SAINT (Bruker, 2006); program(s) used to solve structure: SIR97 (Altomare et al., 1999); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: PLATON (Spek, 2009); software used to prepare material for publication: PLATON (Spek, 2009).

Figures top

Fig. 1. Crystal structure (oder molecular structure) of the title compound with labeling and displacement ellipsoids drawn at the 50% probability level.

tert-Butyl N-[(3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl]-N-methylcarbamate top

Crystal data top

C₁₅H₂₅N₃O₃	F(000) = 320
M_r = 295.38	D_x = 1.190 Mg m⁻³
Monoclinic, P2₁	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: P 2yb	Cell parameters from 1671 reflections
a = 7.1786 (11) Å	θ = 2.6–27.7°
b = 7.3213 (10) Å	µ = 0.08 mm⁻¹
c = 16.042 (2) Å	T = 173 K
β = 102.196 (4)°	Block, colourless
V = 824.1 (2) Å³	0.60 × 0.35 × 0.10 mm
Z = 2

Data collection top

Bruker SMART APEXII diffractometer	1818 reflections with I > 2σ(I)
Radiation source: sealed Tube	R_int = 0.031
Graphite monochromator	θ_max = 27.8°, θ_min = 2.6°
CCD scan	h = −8→9
5061 measured reflections	k = −9→9
2115 independent reflections	l = −19→21

Refinement top

Refinement on F²	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F² > 2σ(F²)] = 0.038	Hydrogen site location: inferred from neighbouring sites
wR(F²) = 0.101	H-atom parameters constrained
S = 1.03	w = 1/[σ²(F_o²) + (0.0542P)² + 0.0849P] where P = (F_o² + 2F_c²)/3
2115 reflections	(Δ/σ)_max = 0.001
195 parameters	Δρ_max = 0.24 e Å⁻³
1 restraint	Δρ_min = −0.17 e Å⁻³

Crystal data top

C₁₅H₂₅N₃O₃	V = 824.1 (2) Å³
M_r = 295.38	Z = 2
Monoclinic, P2₁	Mo Kα radiation
a = 7.1786 (11) Å	µ = 0.08 mm⁻¹
b = 7.3213 (10) Å	T = 173 K
c = 16.042 (2) Å	0.60 × 0.35 × 0.10 mm
β = 102.196 (4)°

Data collection top

Bruker SMART APEXII diffractometer	1818 reflections with I > 2σ(I)
5061 measured reflections	R_int = 0.031
2115 independent reflections

Refinement top

R[F² > 2σ(F²)] = 0.038	1 restraint
wR(F²) = 0.101	H-atom parameters constrained
S = 1.03	Δρ_max = 0.24 e Å⁻³
2115 reflections	Δρ_min = −0.17 e Å⁻³
195 parameters

Special details top

Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes.

Refinement. Refinement of F² against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F², conventional R-factors R are based on F, with F set to zero for negative F². The threshold expression of F² > σ(F²) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F² are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å²) top

	x	y	z	U_iso*/U_eq
C1	0.4456 (3)	0.3404 (3)	0.18701 (13)	0.0302 (4)
H1	0.4716	0.2110	0.1731	0.036*
C2	0.6397 (3)	0.4395 (4)	0.20174 (18)	0.0405 (6)
H2	0.7050	0.3945	0.1564	0.049*
C3	0.6252 (3)	0.6475 (3)	0.19155 (17)	0.0399 (6)
H3A	0.5813	0.7008	0.2408	0.048*
H3B	0.7528	0.6983	0.1911	0.048*
C4	0.4877 (3)	0.7001 (3)	0.10969 (16)	0.0395 (5)
H4A	0.4737	0.8346	0.1066	0.047*
H4B	0.5387	0.6592	0.0601	0.047*
N5	0.3008 (3)	0.6153 (3)	0.10671 (12)	0.0312 (4)
C6	0.3066 (3)	0.4151 (3)	0.10847 (14)	0.0330 (5)
H6A	0.3449	0.3702	0.0563	0.040*
H6B	0.1772	0.3677	0.1081	0.040*
N7	0.3602 (2)	0.3322 (2)	0.26269 (11)	0.0285 (4)
C8	0.2959 (4)	0.4987 (3)	0.29674 (17)	0.0402 (6)
H8A	0.3926	0.5941	0.2989	0.060*
H8B	0.2757	0.4757	0.3544	0.060*
H8C	0.1760	0.5388	0.2599	0.060*
C9	0.3408 (3)	0.1672 (3)	0.29731 (13)	0.0290 (4)
O10	0.3892 (2)	0.0216 (2)	0.27102 (10)	0.0394 (4)
O11	0.2571 (2)	0.1828 (2)	0.36532 (10)	0.0372 (4)
C12	0.2052 (3)	0.0207 (3)	0.40890 (14)	0.0375 (5)
C13	0.3833 (4)	−0.0846 (4)	0.45076 (17)	0.0512 (7)
H13A	0.4434	−0.1362	0.4066	0.077*
H13B	0.3482	−0.1836	0.4856	0.077*
H13C	0.4728	−0.0019	0.4870	0.077*
C14	0.0646 (4)	−0.0948 (4)	0.34738 (17)	0.0433 (6)
H14A	0.1261	−0.1424	0.3028	0.065*
H14B	−0.0455	−0.0200	0.3212	0.065*
H14C	0.0221	−0.1970	0.3782	0.065*
C15	0.1100 (5)	0.1057 (4)	0.47614 (17)	0.0496 (7)
H15A	0.2007	0.1864	0.5130	0.074*
H15B	0.0697	0.0088	0.5106	0.074*
H15C	−0.0014	0.1765	0.4480	0.074*
C16	0.7654 (4)	0.3823 (5)	0.2870 (2)	0.0702 (10)
H16A	0.8933	0.4337	0.2919	0.105*
H16B	0.7736	0.2487	0.2898	0.105*
H16C	0.7099	0.4277	0.3338	0.105*
C17	0.1318 (3)	0.7016 (3)	0.09444 (12)	0.0283 (4)
O18	−0.0215 (2)	0.6227 (2)	0.08811 (11)	0.0374 (4)
C19	0.1360 (3)	0.9103 (3)	0.09008 (14)	0.0340 (5)
H19A	0.2374	0.9573	0.1369	0.041*
H19B	0.1669	0.9482	0.0353	0.041*
C20	−0.0465 (4)	0.9893 (3)	0.09718 (15)	0.0372 (5)
N21	−0.1875 (3)	1.0566 (3)	0.10290 (15)	0.0513 (6)

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
C1	0.0333 (10)	0.0234 (10)	0.0361 (11)	0.0038 (9)	0.0125 (8)	−0.0038 (9)
C2	0.0278 (11)	0.0393 (14)	0.0574 (15)	0.0051 (10)	0.0160 (10)	−0.0009 (12)
C3	0.0269 (10)	0.0385 (14)	0.0575 (15)	−0.0046 (10)	0.0159 (10)	−0.0048 (11)
C4	0.0391 (11)	0.0325 (12)	0.0511 (14)	−0.0060 (10)	0.0187 (10)	0.0034 (11)
N5	0.0344 (9)	0.0239 (9)	0.0359 (10)	−0.0030 (8)	0.0091 (7)	0.0008 (8)
C6	0.0429 (12)	0.0234 (10)	0.0331 (11)	−0.0014 (9)	0.0090 (9)	−0.0037 (9)
N7	0.0327 (8)	0.0233 (9)	0.0310 (9)	0.0052 (8)	0.0099 (7)	−0.0018 (8)
C8	0.0558 (14)	0.0215 (11)	0.0508 (14)	0.0034 (10)	0.0282 (11)	−0.0025 (10)
C9	0.0314 (9)	0.0258 (10)	0.0289 (10)	0.0031 (9)	0.0038 (8)	−0.0018 (9)
O10	0.0546 (10)	0.0241 (8)	0.0414 (9)	0.0088 (8)	0.0147 (7)	−0.0021 (7)
O11	0.0570 (9)	0.0218 (7)	0.0366 (8)	0.0036 (8)	0.0187 (7)	0.0002 (7)
C12	0.0557 (13)	0.0239 (11)	0.0341 (12)	0.0063 (11)	0.0124 (10)	0.0032 (10)
C13	0.0667 (17)	0.0402 (13)	0.0417 (14)	0.0094 (13)	0.0000 (12)	0.0058 (12)
C14	0.0537 (14)	0.0294 (11)	0.0482 (14)	−0.0010 (11)	0.0138 (11)	−0.0000 (11)
C15	0.0788 (18)	0.0346 (12)	0.0431 (14)	0.0021 (13)	0.0300 (13)	0.0024 (11)
C16	0.0317 (12)	0.070 (2)	0.099 (3)	0.0032 (14)	−0.0084 (14)	0.015 (2)
C17	0.0360 (10)	0.0258 (10)	0.0230 (10)	−0.0026 (9)	0.0059 (8)	−0.0023 (8)
O18	0.0355 (8)	0.0322 (8)	0.0445 (9)	−0.0042 (7)	0.0085 (7)	−0.0065 (7)
C19	0.0398 (12)	0.0286 (11)	0.0321 (11)	−0.0018 (10)	0.0044 (9)	0.0035 (9)
C20	0.0506 (14)	0.0270 (11)	0.0325 (11)	0.0005 (11)	0.0058 (10)	−0.0004 (9)
N21	0.0589 (13)	0.0413 (13)	0.0545 (13)	0.0095 (12)	0.0139 (11)	−0.0015 (11)

Geometric parameters (Å, º) top

C1—N7	1.472 (3)	C9—O11	1.357 (3)
C1—C6	1.533 (3)	O11—C12	1.465 (3)
C1—C2	1.544 (3)	C12—C14	1.512 (4)
C1—H1	1.0000	C12—C13	1.522 (3)
C2—C16	1.529 (4)	C12—C15	1.526 (3)
C2—C3	1.533 (4)	C13—H13A	0.9800
C2—H2	1.0000	C13—H13B	0.9800
C3—C4	1.516 (4)	C13—H13C	0.9800
C3—H3A	0.9900	C14—H14A	0.9800
C3—H3B	0.9900	C14—H14B	0.9800
C4—N5	1.470 (3)	C14—H14C	0.9800
C4—H4A	0.9900	C15—H15A	0.9800
C4—H4B	0.9900	C15—H15B	0.9800
N5—C17	1.345 (3)	C15—H15C	0.9800
N5—C6	1.467 (3)	C16—H16A	0.9800
C6—H6A	0.9900	C16—H16B	0.9800
C6—H6B	0.9900	C16—H16C	0.9800
N7—C9	1.349 (3)	C17—O18	1.228 (3)
N7—C8	1.451 (3)	C17—C19	1.530 (3)
C8—H8A	0.9800	C19—C20	1.459 (3)
C8—H8B	0.9800	C19—H19A	0.9900
C8—H8C	0.9800	C19—H19B	0.9900
C9—O10	1.223 (3)	C20—N21	1.147 (3)

N7—C1—C6	112.35 (17)	O10—C9—O11	123.9 (2)
N7—C1—C2	114.38 (18)	N7—C9—O11	110.90 (18)
C6—C1—C2	111.59 (19)	C9—O11—C12	121.04 (17)
N7—C1—H1	105.9	O11—C12—C14	110.10 (18)
C6—C1—H1	105.9	O11—C12—C13	110.3 (2)
C2—C1—H1	105.9	C14—C12—C13	112.8 (2)
C16—C2—C3	112.4 (2)	O11—C12—C15	101.76 (19)
C16—C2—C1	110.6 (2)	C14—C12—C15	110.7 (2)
C3—C2—C1	114.31 (19)	C13—C12—C15	110.8 (2)
C16—C2—H2	106.3	C12—C13—H13A	109.5
C3—C2—H2	106.3	C12—C13—H13B	109.5
C1—C2—H2	106.3	H13A—C13—H13B	109.5
C4—C3—C2	111.2 (2)	C12—C13—H13C	109.5
C4—C3—H3A	109.4	H13A—C13—H13C	109.5
C2—C3—H3A	109.4	H13B—C13—H13C	109.5
C4—C3—H3B	109.4	C12—C14—H14A	109.5
C2—C3—H3B	109.4	C12—C14—H14B	109.5
H3A—C3—H3B	108.0	H14A—C14—H14B	109.5
N5—C4—C3	110.11 (18)	C12—C14—H14C	109.5
N5—C4—H4A	109.6	H14A—C14—H14C	109.5
C3—C4—H4A	109.6	H14B—C14—H14C	109.5
N5—C4—H4B	109.6	C12—C15—H15A	109.5
C3—C4—H4B	109.6	C12—C15—H15B	109.5
H4A—C4—H4B	108.2	H15A—C15—H15B	109.5
C17—N5—C6	119.57 (19)	C12—C15—H15C	109.5
C17—N5—C4	126.53 (19)	H15A—C15—H15C	109.5
C6—N5—C4	113.55 (19)	H15B—C15—H15C	109.5
N5—C6—C1	112.52 (19)	C2—C16—H16A	109.5
N5—C6—H6A	109.1	C2—C16—H16B	109.5
C1—C6—H6A	109.1	H16A—C16—H16B	109.5
N5—C6—H6B	109.1	C2—C16—H16C	109.5
C1—C6—H6B	109.1	H16A—C16—H16C	109.5
H6A—C6—H6B	107.8	H16B—C16—H16C	109.5
C9—N7—C8	121.94 (17)	O18—C17—N5	123.7 (2)
C9—N7—C1	118.25 (17)	O18—C17—C19	119.5 (2)
C8—N7—C1	119.80 (18)	N5—C17—C19	116.7 (2)
N7—C8—H8A	109.5	C20—C19—C17	111.4 (2)
N7—C8—H8B	109.5	C20—C19—H19A	109.3
H8A—C8—H8B	109.5	C17—C19—H19A	109.3
N7—C8—H8C	109.5	C20—C19—H19B	109.3
H8A—C8—H8C	109.5	C17—C19—H19B	109.3
H8B—C8—H8C	109.5	H19A—C19—H19B	108.0
O10—C9—N7	125.24 (18)	N21—C20—C19	177.9 (3)

N7—C1—C2—C16	43.0 (3)	C2—C1—N7—C8	67.0 (3)
C6—C1—C2—C16	171.9 (2)	C8—N7—C9—O10	178.8 (2)
N7—C1—C2—C3	−85.0 (3)	C1—N7—C9—O10	0.2 (3)
C6—C1—C2—C3	43.9 (3)	C8—N7—C9—O11	−0.3 (3)
C16—C2—C3—C4	−175.6 (2)	C1—N7—C9—O11	−178.92 (17)
C1—C2—C3—C4	−48.5 (3)	O10—C9—O11—C12	−4.7 (3)
C2—C3—C4—N5	55.2 (3)	N7—C9—O11—C12	174.44 (18)
C3—C4—N5—C17	126.0 (2)	C9—O11—C12—C14	−60.1 (3)
C3—C4—N5—C6	−60.9 (3)	C9—O11—C12—C13	65.0 (3)
C17—N5—C6—C1	−129.3 (2)	C9—O11—C12—C15	−177.46 (19)
C4—N5—C6—C1	57.1 (3)	C6—N5—C17—O18	3.4 (3)
N7—C1—C6—N5	83.0 (2)	C4—N5—C17—O18	176.1 (2)
C2—C1—C6—N5	−47.0 (3)	C6—N5—C17—C19	−177.8 (2)
C6—C1—N7—C9	117.2 (2)	C4—N5—C17—C19	−5.1 (3)
C2—C1—N7—C9	−114.3 (2)	O18—C17—C19—C20	12.5 (3)
C6—C1—N7—C8	−61.5 (3)	N5—C17—C19—C20	−166.36 (18)

Experimental details

Crystal data
Chemical formula	C₁₅H₂₅N₃O₃
M_r	295.38
Crystal system, space group	Monoclinic, P2₁
Temperature (K)	173
a, b, c (Å)	7.1786 (11), 7.3213 (10), 16.042 (2)
β (°)	102.196 (4)
V (Å³)	824.1 (2)
Z	2
Radiation type	Mo Kα
µ (mm⁻¹)	0.08
Crystal size (mm)	0.60 × 0.35 × 0.10

Data collection
Diffractometer	Bruker SMART APEXII
Absorption correction	–
No. of measured, independent and observed [I > 2σ(I)] reflections	5061, 2115, 1818
R_int	0.031
(sin θ/λ)_max (Å⁻¹)	0.657

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.038, 0.101, 1.03
No. of reflections	2115
No. of parameters	195
No. of restraints	1
H-atom treatment	H-atom parameters constrained
Δρ_max, Δρ_min (e Å⁻³)	0.24, −0.17

Computer programs: APEX2 (Bruker, 2006), SAINT (Bruker, 2006), SIR97 (Altomare et al., 1999), SHELXL97 (Sheldrick, 2008), PLATON (Spek, 2009).

Acknowledgements

The authors thank Ellen Pfaffenrot and Peter Keck for fruitful discussions and suggestions and acknowledge support by the Deutsche Forschungsgemeinschaft and the Open Access Publishing Fund of Tübingen University.

References

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