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American International Journal of Research in Formal, Applied & Natural Sciences

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ISSN (Print): 2328-3777, ISSN (Online): 2328-3785, ISSN (CD-ROM): 2328-3793 AIJRFANS is a refereed, indexed, peer-reviewed, multidisciplinary and open access journal published by International Association of Scientific Innovation and Research (IASIR), USA (An Association Unifying the Sciences, Engineering, and Applied Research)

(3α, 16α)-Eburnamenine-14-Carboxylic acid Ethyl ester Mishra Bharti, Tiwari R.K. S.O.S.Physics, Jiwaji University – 474011, Gwalior (M.P.), INDIA Abstract: The title compound is Ethyl apovincaminate, a semi synthetic derivative of the alkaloid Vincamine, an extract from the Periwinkle plant. Vinpocetine was first isolated from the plant in 1975 by the Hungarian chemist Csaba Szantay. Single crystal X-ray diffraction study showed the unit cell parameters as a=8.8974(3), b= 9.5347(3), c= 11.2853(3) Å and β=106.536(1)° with Z=2. It belongs to monoclinic crystal system with space group P21/c. In all total with 4090 unique reflections, the final R value is 0.022. Kew Words: Vincamine, single, crystal etc. I. Introduction Vinpocetine (C22H26N2O2), chemically known as Ethyl apovincaminate is a semi synthetic derivative of the alkaloid Vincamine, an extract from the periwinkle plant. Vinpocetine was first isolated from the plant in 1975 by the Hungarian chemist Csaba Szantay. The production of the drug was started in 1978 by Richter Gedeon Rt, on Hungarian pharmaceutical company. Non- clinical and clinical studies have suggested multiple mechanisms responsible for the beneficial neuroprotective effects of Vinpocetine. As no significant side effects related to Vinpocetine treatment have been reported, it is considered to be safe for long-term use. This Visoactive alkaloid is widely marketed as a supplement for Vasodilation and as a nootropic for the improvement of memory. The present review focuses X-ray crystallographic studies on Vinpocetine This drug has been identified as a potential role in the treatment of Parkinson disease and Alzheimer disease. Vinpocetine is generally well-tolerated in humans. No serious side effects have thus far been noted in clinical trials although none of these trials were long-term. Some users have reported headaches, especially at doses above 15 milligrams per day, as well as occasional upset stomach. Adverse drug-herb interactions have not been prevalent, and vinpocetine appears safe to take with other medications, including diabetes drugs. Vinpocetine is an interesting compound which still challenges scientists and clinicians worldwide. New informations obtained from recent, ongoing and future studies might help to understand the molecular mechanism of the drug’s action and to determine the conditions in which vinpocetine can mostly exert its beneﬁcial therapeutic effect. Looking into its medicinal use, authors have decided to find out its three dimensional crystal structure. II. Experimental The IUPAC name of the Vinpocetine is (3α, 16α)-Eburnamenine-14-carboxylic acid ethyl ester. The molecular mass is 350.45 g/mol. and melting point is 373 K. Extremely beautiful transparent, colorless crystals were grown at room temperature by slow evaporation from its solution in Ethyl alcohol at room temperature. The grown crystals diffracted well. The density was measured at room temperature by floatation method in a mixture of Benzene and Carbon tetrachloride.. The measured density is 1.262 Mg/m3. The complete preliminary data is shown in Table 1. The chemical structure of the molecule is shown in Fig 1. III. Intensity Data collection and solution The three dimensional intensity data were collected, on a computerized automatic Bruker axs Kappa apex 2 CCD diffractometer using graphite filtered Mokα radiation (0.7107 Å) at Sardar Patel University, Vallabh Vidyanagar, Gujarat. The temperature of data collection was 293k. All the data were corrected for Lorentz and polarization effects but no absorption correction was done because of very small absorption coefficient. The data collection was done by a θ range of 2.4 to 27.5˚. In all 8131 reflections were collected out of which 4090 were unique. The diffraction data showed a=8.8974(3), b=9.5347(3), c=11.2853(3) Å, β=106.536˚(1) and Z=2. The crystals class was monoclinic with space group P21. The data collection was done for h ranging from -11 to 11, k from -12 to 12 and l from -14 to 14. Each intensity measurement involved in a scan over the reflection peak height, a background measurement of the peak height. The structure was using SHELXS-97 [1] program for crystal structure solution.

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IV. Refinement The positional parameters which were obtained from SHELXS-97 and their isotropic temperature factors were refined by SHELXL-97 [2] refinement program. After several cycles of initial refinement the R factor dropped to 0.0381. The refinement was carried out using Full matrix least square technique. There after the refinement was carried out with individual anisotropic temperature factors of the form: Exp. [-(U11h2+U22k2+U33l2+2U12hk+2U23kl+2U13hl)] reduced R-factor to 0.0293. At this stage the hydrogen atoms were fixed by geometrical considerations and refined subsequently with isotropic temperature factors of the corresponding non- hydrogen atoms. Refinement was further carried out for two more cycles till all the shift on the parameters became much smaller than the corresponding e.s.d’s. Refinement of F2 is against all reflections. The weighted R-factor wR and goodness of fit s are based on F2, conventional R-factors are based on F, with F set to zero for negative F 2. The threshold expression of F2> 2 sigma (F2) is used only for calculating R-factors (gt) etc. and is not relevant to the choice of reflections for refinement. Rfactors based on F2 are statistically about twice as large as those as based on F and R-factors based on all data will be even larger. The final value of R-factor is 0.022 for all the observed 4090 unique reflections. The final positional of non-hydrogen atoms are listed in Table 2. V. Results and discussion The numbering scheme and ORTEP [3] view of the molecule is shown in Fig 2. The bond lengths and angles involving non-hydrogen atoms are listed in Tables 3 As far as bond lengths and angles of the Benzene rings are concerned, they seems to be normal as compared to other related structures [4]-[6]. The widening of C(8)-N(1)C(11) angle of 126.55˚ and shrinking of C(9)-C(10)-N(2) of 115.60˚ seems to be a characteristic feature of such molecules and may probably results from the steric hindrance of dissimilar groups described by Bartell [7]. The C(18)-O(1) bond distance of 1.2042 Å is comparatively short indicating a considerable amount of π bond character in it. The all other angles in the 5-member ring are in the vicinity of 107.62˚ as usual. The molecule seems to be suffering from distortions as we look into the non-bonded distances O(1)-C(5)= 3.0039, O(1)-C(4)= 3.1328, C(5)-C(18)= 3.2736 and C(8)-C(17)= 3.2935Å. The all other non-bonded (Vander Walls) contacts with symmetry related molecules are listed in Table 4. The molecule is twisted and folded because the plane of the Benzene ring (C(11)-C(14)-C(15)-C(16)-C(17)-N(2)) is inclined to the plane of the rest of the rings with an angle of 76.6˚(2). Similarly the chain C(14)-C(21)-C(22) is also inclined with an angle of 110.89˚ with the Benzene ring to which it is attached. The various torsional angles are shown in Table 5. There is only an intra-molecular hydrogen bond in the structure (Table 6). The molecular packing’s along various axes are shown in Figs 3 to 5. We can therefore conclude that the crystal structure is stabilized by network of hydrogen bond and Vander Walls forces. VI.

References

[1]. G.M Sheldrich, “ SHELXS-97, Program for the solution of crystal structure” 1997. [2]. G.M Sheldrich, “SHELXL-97, Program for crystal structure determination” 1997. [3]. C.K.,Johnson, “ORTEP Report ORNL-3794 Ook Ridge National Laboratory, Tennessee,U.S.A”, 1954. [4]. J.Fayos and M.M.Ripoll,Acta Cryst. B37, 760-763,1981. [5]. H.K.Fun, S. Laphookhieo, W. Maneerat, and S.Chantrapromma,Acta Cryst. E63, 3964-3965, 2007. [6]. D.L.Wang, X.H. Cai, P.Huang, and H.P. Huang,Acta Cryst.Sec E69, 0833, 2013. [7]. L.S. Bartell, Tetrahedran, 17, 177, 1962.

Fig 1 Molecular structure of Vinpocetine

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Table 1 Preliminary data of Vinpocetine Identification Name

Vinpocetine

Empirical formula

C22H26N2O2

Formula weight

350.46

Temperature

293(2) K

Wavelength

0.71073 Å (Mokα)

Crystal system, space group

monoclinic, P21

Unit cell dimensions

a=8.8974 a=8.8974(3) Å, b=9.5347(3)Å c=11.2853(3) Å, β=106.536˚(1)

Volume

971.78(5) Å3

Z, Calculated density

2, 1.268 Mg/m3

Absorption coefficient

0.08 mm-1

F(000)

376

Theta range for data collection

2.4 to 27.5 deg

Limiting indices

-11<=h<=11, -12<=k<=12, -14<=l<=14

Reflections collected / unique

4090 / 3900 [R(int) = 0.022]

Completeness to theta

27.5

Refinement method

Full-matrix least-squares on F2

Data / restraints / parameters

3900 / 1 / 236

Goodness-of-fit on F2

1.075

Final R indices [I>2sigma (I)]

R1 = 0.0469, wR2 = 0.1413

R indices (all data)

R1 = 0.0487, wR2 = 0.1443

Largest diff. peak and ho

0.41 and -0.40 e.Å

99.0 %

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Fig.2 ORTEP view and numbering scheme seen down c-axis

Fig. 4 Packing of the molecule seen down b-axis

Table 2 Atomic coordinates (x 104) Atom O(1) O(2) N(1) N(2) C(1) C(2) C(3) C(4) C(5) C(6) C(7) C(8) C(9) C(10) C(11) C(12) C(13) C(14) C(15) C(16) C(17) C(18) C(19) C(20) C(21) C(22)

x 0.41899 0.50339 0.20977 0.23534 -0.16019 -0.12420 0.00915 0.10641 0.06845 -0.06491 0.23314 0.07815 0.02809 0.15920 0.31863 0.44131 0.36394 0.39406 0.27135 0.19816 0.12305 0.42976 0.58243 0.65971 0.53926 0.62353

Fig.3 Packing of the molecule seen down a-axis

Fig. 5 Packing of the molecule seen down a-axis

( 2 x103) for non-hydrogen atoms. U (eq) is defined as one third of the trace of the orthogonalized Uij tensor. y z Ueq 0.70798 0.46682 0.0550 0.79423 0.31292 0.0419 0.37140 0.25594 0.0448 0.17680 0.12441 0.0423 0.56798 0.41512 0.0636 0.44146 0.36949 0.0539 0.43208 0.32771 0.0423 0.55128 0.33568 0.0403 0.67999 0.37814 0.0510 0.68590 0.41717 0.0622 0.51049 0.29326 0.0296 0.31890 0.27581 0.0420 0.17078 0.24116 0.0501 0.09449 0.20172 0.0517 0.29642 0.19865 0.0351 0.53036 0.20052 0.0367 0.58228 0.27675 0.0351 0.39801 0.12452 0.0336 0.43861 0.00166 0.0411 0.30856 -0.07030 0.0481 0.21812 0.00881 0.0510 0.70099 0.36301 0.0379 0.90615 0.39556 0.0412 0.99861 0.32381 0.0542 0.32369 0.10412 0.0402 0.39880 0.02336 0.0611

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Table 3 Bond lengths O(1)-C(18) O(2)-C(18) O(2)-C(19) N(1)-C(7) N(1)-C(8) N(1)-C(11) N(2)-C(10) N(2)-C(11) N(2)-C(17) C(1)-C(2) C(1)-C(6) C(2)-C(3) C(3)-C(4) C(3)-C(8) C(4)-C(5) C(4)-C(7) C(5)-C(6) C(7)-C(13) C(8)-C(9) C(9)-C(10) C(11)-C(14) C(12)-C(13) C(12)-C(14) O(1)—C(18)—C(13) O(2)—C(18)—C(13) O(2)—C(19)—C(20) C(14)—C(21)—C(22) N(1)—C(8)—C(3) N(1)—C(8)—C(9) C(3)—C(8)—C(9) C(8)—C(9)—C(10) N(2)—C(10)—C(9) N(1)—C(11)—N(2) N(1)—C(11)—C(14) N(2)—C(11)—C(14)

]

1.2042 1.3228 1.4593 1.3891 1.3497 1.4912 1.4740 1.4828 1.4537 1.3845 1.4043 1.3987 1.4158 1.4454 1.3935 1.3997 1.3793 1.4074 1.4989 1.5439 1.5518 1.3402 1.5164 123.30 112.30 107.35 116.77 106.21 120.90 132.86 109.05 115.60 109.39 111.62 113.50

˚] f

-hydrogen atoms.

C(2)—C(1)—C(6) C(1)—C(2)—C(3) C(2)—C(3)—C(4) C(2)—C(3)—C(8) C(4)—C(3)—C(8) C(3)—C(4)—C(5) C(3)—C(4)—C(7) C(5)—C(4)—C(7) C(4)—C(5)—C(6) C(1)—C(6)—C(5) N(1)—C(7)—C(4) N(1)—C(7)—C(13) C(4)—C(7)—C(13) C(13)—C(12)—C(14) C(7)—C(13)—C(12) C(7)—C(13)—C(18) C(12)—C(13)—C(18) C(11)—C(14)—C(12) C(11)—C(14)—C(15) C(11)—C(14)—C(21) C(12)—C(14)—C(15) C(12)—C(14)—C(21) C(15)—C(14)—C(21) C(14)—C(15)—C(16) C(18)—O(2)—C(19) C(7)—N(1)—C(8) C(7)—N(1)—C(11) C(8)—N(1)—C(11) C(10)—N(2)—C(11) C(10)—N(2)—C(17) C(11)—N(2)—C(17) C(15)—C(16)—C(17) N(2)—C(17)—C(16) O(1)—C(18)—O(2)

120.08 119.29 119.28 133.10 107.62 121.68 107.01 131.30 117.42 122.16 107.66 118.83 133.40 124.06 120.03 117.79 121.24 107.90 109.61 107.58 108.02 110.89 112.74 111.04 115.19 111.46 121.97 126.55 108.37 111.17 113.82 109.89 112.01 124.38

Table 4 Non-Bonded Contact Distances [Å] O(1)…C(4) O(1)…C(5) O(1)…C(19)_ O(1)…C(20)_ C(2)…C(6)_ C(4)…O(1) C(5)…C(18) C(5)…O(1) C(6)…C(2)_b C(7)…C(19)_ C(7)…C(15) C(8)…C(17) C(15)…C(7) C(17)…C(8) C(18)…C(5) C(19)…C(7)_h C(19)…O(1)_h C(20)…O(1)_h

3.1328 3.0039 3.2720 3.3167 3.5014 3.1328 3.2736 3.0039 3.5014 3.5686 3.4716 3.2935 3.4716 3.2935 3.2736 3.5686 3.2720 3.3167

a =[ 2646.00 ] = 1-x,-1/2+y,1-z b =[ 2556.00 ] = -x,1/2+y,1-z c =[ 1455.00 ] = -1+x,y,z

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d =[ 2546.00 ] = -x,-1/2+y,1-z e =[ 2555.00 ] = -x,1/2+y,-z f =[ 2645.00 ] = 1-x,-1/2+y,-z g =[ 1655.00 ] = 1+x,y,z h =[ 2656.00 ] = 1-x,1/2+y,1-z i =[ 2545.00 ] = -x,-1/2+y,-z j =[ 2655.00 ] = 1-x,1/2+y,-z

Table 5 Torsion angles [deg]

C(19)—O(2)—C(18)—C(13) C(18)—O(2)—C(19)—C(20) C(19)—O(2)—C(18)—O(1) C(8)—N(1)—C(11)—C(14) C(7)—N(1)—C(11)—N(2) C(11)—N(1)—C(8)—C(9) C(11)—N(1)—C(7)—C(13) C(7)—N(1)—C(11)—C(14) C(8)—N(1)—C(7)—C(4) C(7)—N(1)—C(8)—C(9) C(7)—N(1)—C(8)—C(3) C(7)—N(1)—C(8)—C(3) C(11)—N(1)—C(8)—C(3) C(11)—N(1)—C(7)—C(4) C(8)—N(1)—C(7)—C(13) C(8)—N(1)—C(11)—N(2) C(10)—N(2)—C(11)—C(14) C(11)—N(2)—C(17)—C(16) C(10)—N(2)—C(17)—C(16) C(17)—N(2)—C(11)—N(1) C(11)—N(2)—C(10)—C(9) C(17)—N(2)—C(10)—C(9) C(10)—N(2)—C(11)—N(1) C(17)—N(2)—C(11)—C(14) C(2)—C(1)—C(6)—C(5) C(6)—C(1)—C(2)—C(3) C(1)—C(2)—C(3)—C(8) C(1)—C(2)—C(3)—C(4) C(2)—C(3)—C(4)—C(7) C(4)—C(3)—C(8)—C(9) C(4)—C(3)—C(8)—N(1) C(2)—C(3)—C(8)—C(9) C(8)—C(3)—C(4)—C(5) C(2)—C(3)—C(4)—C(5) C(2)—C(3)—C(8)—N(1) C(8)—C(3)—C(4)—C(7) C(3)—C(4)—C(7)—C(13) C(7)—C(4)—C(5)—C(6)

-174.76 179.20 3.74 147.59 -157.18 0.79 -0.23 -30.73 -2.11 179.26 1.04 1.04 -177.42 176.43 -178.77 21.13 -175.78 54.94 177.65 73.83 64.80 -61.00 -50.40 -51.54 -1.95 1.11 -179.87 1.47 177.32 -177.50 0.40 3.72 177.62 -3.40 -178.37 -1.65 178.24 -178.34

C(5)-C(4)-C(7)-C(13) C(3)-C(4)-C(5)-C(6) C(3)-C(4)-C(7)-N(1) C(5)-C(4)-C(7)-N(1) C(4)-C(5)-C(6)-C(1) N(1)-C(7)-C(13)-C(18) N(1)-C(7)-C(13)-C(12) C(4)-C(7)-C(13)-C(18) C(4)-C(7)-C(13)-C(12) N(1)-C(8)-C(9)-C(10) C(3)-C(8)-C(9)-C(10) C(8)-C(9)-C(10)-N(2) N(1)-C(11)-C(14)-C(15) N(1)-C(11)-C(14)-C(21) N(1)-C(11)-C(14)-C(12) N(2)-C(11)-C(14)-C(21) N(2)-C(11)-C(14)-C(12) N(2)-C(11)-C(14)-C(15) C(13)-C(12)-C(14)-C(15) C(14)-C(12)-C(13)-C(7) C(14)-C(12)-C(13)-C(18) C(13)-C(12)-C(14)-C(11) C(13)-C(12)-C(14)-C(21) C(12)-C(13)-C(18)-O(1) C(12)-C(13)-C(18)-O(2) C(7)-C(13)-C(18)-O(2) C(7)-C(13)-C(18)-O(1) C(12)-C(14)-C(15)-C(16) C(11)-C(14)-C(21)-C(22) C(11)-C(14)-C(15)-C(16) C(21)-C(14)-C(15)-C(16) C(12)-C(14)-C(21)-C(22) C(15)-C(14)-C(21)-C(22) C(14)-C(15)-C(16)-C(17) C(15)-C(16)-C(17)-N(2) C(2)-C(3)-C(8)-N(1) C(8)-C(3)-C(4)-C(7) C(3)-C(4)-C(7)-C(13)

-0.94 2.58 2.27 -176.92 0.09 -152.92 16.10 31.46 -159.52 7.97 -174.37 -41.26 -74.46 162.62 42.94 -73.20 167.11 49.71 86.29 2.22 170.86 -32.13 -149.70 -141.32 37.20 -153.92 27.56 -170.57 174.69 -53.25 66.55 -67.54 53.73 57.43 -57.71 -178.37 -1.65 178.24

Table 6 Hydrogen bonds [Å and deg.] D-H…A

d(D-H)

C(5)—H(5) .. O(1)

0.9300

(H…A) 2.5200

(D…A) 3.0039

<(DHA) 113.

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