CN100393694C - Tetrabenzyl voglibose crystallizing and preparing process - Google Patents
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Abstract
The present invention relates to crystallized (1S)-(1(hydroxy), 2, 4, 5/1, 3)-2, 3, 4-tri-oxo-benzyl-5-[(2-hydroxy-1-(hydroxymethyl) ethyl) amino]-1-carbo-methylbenzylmethyl-1, 2, 3, 4-cyclohexane tetrol, which has smelting point of 89.7 deg.c; monocrystalline X ray diffraction data of orthorhombic system, P2(1)2(1)2(1) space groupp, unit cell parameters a=7.8487, b=20.746, c=20.988 and R 0.0748; and X ray diffraction peak of crystal powder of 16.76, 18.90 and 24.00+/-0.15 deg. It is prepared through dissolving oily tetrabenzyl voglibose in one kind of polar non-protonic solvent, adding one other kind of non-polar solvent via stirring at room temperature to crystallize, stilling, filtering and vacuum drying to obtain the crystal. Compared with oily tetrabenzyl voglibose, the crystallized tetrabenzyl voglibose has higher purity, convenient transportation and maintenance and easy application.
Description
Technical field
The present invention relates to a kind of crystallization of Tetrabenzyl voglibose, this crystallization can be used for preparing highly purified alpha-glucosidase inhibitor----voglibose, and the latter is the active drug that is used for the treatment of diabetes at present.The present invention also relates to this crystalline method of a kind of preparation simultaneously.
Background technology
Voglibose is a kind of alpha-glucosidase inhibitor, is by Japan military field drugmaker exploitation (EP56194), is used for treatment of diabetes in Japan, Korea S and China's listing at present.Its structure is suc as formula shown in (I):
The chemical name of voglibose is (1S)-(1 (hydroxyl), 2,4,5/1,3)-and 5-[(2-hydroxyl-1-(methylol) ethyl) amino]-1-carbon-methylol-1,2,3,4-hexanaphthene tetrol, its manufacture method has several, be to produce valienamine (Valienamine) the earliest, carry out chemical synthesis process manufacturing (patent documentation EP56194) as raw material again by fermentation; But the preparation separating technology of valienamine is loaded down with trivial details, needs a large amount of labour's energy consumptions, and impurity is difficult for removing in the product of this method preparation, needs loaded down with trivial details column chromatogram chromatography to make with extra care work again.Some were arranged afterwards by being that raw material carries out the complete synthesis method of chemistry with D-glucose again, patent documentation EP260121 for example, J.Org.Chem.1992,57,3651, WO03/080561, WO2005/030698 etc.More representational operational path is patent documentation EP260121 and J.Org.Chem.1992,57,3651 disclosed route (see figure 1)s.
In this preparation route, (1S)-(1 (hydroxyl), 2,4,5/1,3)-2,3,4-three-oxygen-benzyl-5-[(2-hydroxyl-1-(methylol) ethyl) amino]-1-carbon-benzyloxymethyl-1,2,3,4-hexanaphthene tetrol (is called for short Tetrabenzyl voglibose (as follows), structure is compound (II)) be a very crucial intermediate, voglibose carries out debenzylation reaction by it exactly and directly prepares to come, so its quality directly has influence on the quality as treatment diabetes medicament voglibose.
Existing document and method (as patent documentation EP260121, J.Org.Chem.1992,57,3651, WO2005/030698) report that this intermediate is the oily product.
Summary of the invention
In order to overcome the weak point that existing oily Tetrabenzyl voglibose quality exists, the object of the present invention is to provide a kind of Tetrabenzyl voglibose of crystalline state.Its crystalline feature is by monocrystalline X-ray diffraction, powder x-ray diffraction, and differential scanning calorimetric analysis (DSC), infrared spectra characterize.
Further aim of the present invention provides Tetrabenzyl voglibose crystalline preparation method, this method steps is few, reagent be simple and easy to, pollution is little, easy and simple to handle, product purity is high.
The present invention also provides the concrete grammar that is prepared voglibose by this crystallization simultaneously.
The present invention is in research voglibose preparation technology's process, prepared crucial intermediate (1S)-(1 (hydroxyl), 2,4,5/1,3)-2,3,4-three-oxygen-benzyl-5-[(2-hydroxyl-1-(methylol) ethyl) amino]-1-carbon-benzyloxymethyl-1,2,3,4-hexanaphthene tetrol (Tetrabenzyl voglibose), common all documents and existing data show that this intermediate is a kind of buttery material, the present invention studies this material, and has successfully obtained the crystallization of this intermediate, and this crystallization is a kind of crystalline state stable under room temperature and usual conditions, by to this crystalline monocrystalline state, pulverulence detects, and has set forth this crystalline feature.Therefore the invention provides based on this crystalline monocrystalline X-ray diffraction, powder x-ray diffraction, DSC, IR collection of illustrative plates and data is the crystallization of a kind of Tetrabenzyl voglibose of feature.Fig. 2 is that the molecule stereographic map that the monocrystalline X-ray diffraction obtains is carried out in the Tetrabenzyl voglibose crystallization; Fig. 3 is a molecule structure cell accumulation graph in the crystal of Tetrabenzyl voglibose; Fig. 4 passes through hydrogen bond action power bonded synoptic diagram between the molecule in the Tetrabenzyl voglibose crystalline structure; Fig. 5 is the x-ray diffraction pattern of Tetrabenzyl voglibose crystalline powder; Fig. 6 is differential scanning calorimetric analysis (DSC) figure of Tetrabenzyl voglibose; Fig. 7 is the infrared spectrogram of Tetrabenzyl voglibose.
By this crystalline monocrystalline X-ray diffraction test is shown that this crystalline molecular formula is C
38H
45NO
7This crystal belongs to rhombic system, P2 (1) 2 (1) 2 (1) spacer, and unit cell parameters is a=7.8487
, b=20.746
, c=20.988
, the R value is 0.0748.The space multistory structure of this molecule as shown in Figure 2; Molecule at the structure cell accumulation graph of A direction as shown in Figure 3; Fig. 4 shows intermolecular by the combination of hydrogen bond action power.
Under tabulate 1---table 6 has been listed crystal data respectively, the data of atomic coordinate, bond distance, bond angle, torsional angle, hydrogen bond bond distance bond angle.
Table 1. crystal data and structural modifications data (Crystal data and structure refinement)
Table 2. atomic coordinate and anisotropic temperature parameter (Atomic coordinates (* 10
4) andequivalent isotropic displacement parameters (
2* 10
3) .U (eq) isdefined as one third of the trace of the orthogonalized Uij tensor.)
| Atom (Atom) | x | y | z | U(eq) |
| N(1) | 5785(6) | -985(2) | 9877(2) | 40(1) |
| O(1) | 9116(5) | -631(1) | 10222(2) | 40(1) |
| O(2) | 8817(6) | 667(2) | 11368(2) | 56(1) |
| O(3) | 10227(4) | 666(2) | 9853(2) | 42(1) |
| O(4) | 7531(5) | 865(2) | 8953(2) | 41(1) |
| O(5) | 4948(4) | -87(2) | 8950(2) | 41(1) |
| O(6) | 4900(8) | -2648(2) | 10350(3) | 101(2) |
| O(7) | 2146(5) | -1327(2) | 9956(2) | 57(1) |
| C(1) | 8413(6) | -50(3) | 10476(2) | 34(1) |
| C(2) | 8503(6) | 498(3) | 9981(2) | 34(1) |
| C(3) | 7546(7) | 324(2) | 9378(2) | 31(1) |
| C(4) | 5704(7) | 156(3) | 9531(2) | 35(1) |
| C(5) | 5419(6) | -317(3) | 10082(3) | 34(1) |
| C(6) | 6530(7) | -135(3) | 10654(2) | 38(1) | |||
| C(7) | 9481(7) | 109(3) | 1065(3) | 45(2) | |||
| C(8) | 9567(9) | 789(3) | 11965(3) | 62(2) | |||
| C(9) | 8629(8) | 1328(3) | 12296(3) | 47(2) | |||
| C(10) | 8259(10) | 1277(4) | 12928(3) | 71(2) | |||
| C(11) | 7396(13) | 1763(5) | 13246(4) | 96(3) | |||
| C(12) | 6883(12) | 2316(5) | 12911(5) | 103(3) | |||
| C(13) | 7275(13) | 2360(4) | 12273(4) | 94(3) | |||
| C(14) | 8130(10) | 1869(4) | 11977(4) | 72(2) | |||
| C(15) | 10541(9) | 1324(4) | 9762(6) | 110(4) | |||
| C(16) | 12286(7) | 1518(3) | 9942(3) | 43(2) | |||
| C(17) | 12841(10) | 1457(4) | 10561(4) | 71(2) | |||
| C(18) | 14385(15) | 1641(4) | 10758(6) | 109(3) | |||
| C(19) | 15420(11) | 1910(4) | 10347(6) | 89(3) | |||
| C(20) | 15112(12) | 1989(3) | 9718(6) | 89(3) | |||
| C(21) | 13399(11) | 1785(3) | 9497(4) | 71(2) | |||
| C(22) | 8099(9) | 752(3) | 8335(3) | 59(2) | |||
| C(23) | 7695(7) | 1317(3) | 7910(3) | 46(2) | |||
| C(24) | 7829(10) | 1947(4) | 8117(4) | 71(2) | |||
| C(25) | 7430(14) | 2454(4) | 7715(4) | 93(3) | |||
| C(26) | 6907(12) | 2320(6) | 7103(5) | 98(3) | |||
| C(27) | 6868(14) | 1723(6) | 6893(5) | 106(3) | |||
| C(28) | 7229(12) | 1211(5) | 7295(4) | 87(3) | |||
| C(29) | 3134(9) | -57(5) | 8936(4) | 99(3) | |||
| C(30) | 2531(8) | -35(4) | 8259(3) | 47(2) | |||
| C(31) | 2904(12) | 484(5) | 7907(5) | 96(3) | |||
| C(32) | 2326(16) | 551(8) | 7321(6) | 151(6) | |||
| C(33) | 1265(13) | 70(8) | 7107(5) | 142(7) | |||
| C(34) | 793(13) | -494(8) | 7395(8) | 164(8) | |||
| C(35) | 1548(11) | -504(5) | 8048(5) | 94(3) | |||
| C(36) | 5090(8) | -1500(3) | 10286(3) | 44(2) |
| C(37) | 5345(9) | -2125(3) | 9945(4) | 66(2) |
| C(38) | 3232(8) | -1421(3) | 10485(3) | 53(2) |
Table 3. bond distance (Bond lengths [
])
| Atom-atom (Atom-atom) | Length (Length) | Atom-atom (Atom-atom) | Length (Length) | Atom-atom (Atom-atom) | Length (Length) | ||||
| N(1)-C(36) | 1.475(7) | C(8)-C(9) | 1.508(9) | C(23)-C(24) | 1.380(10) | ||||
| N(1)-C(5) | 1.480(7) | C(8)-H(8A) | 0.9700 | C(24)-C(25) | 1.384(11) | ||||
| N(1)-H(1B) | 1.01(6) | C(8)-H(8B) | 0.9700 | C(24)-H(24A) | 0.9300 | ||||
| O(1)-C(1) | 1.429(6) | C(9)-C(14) | 1.361(9) | C(25)-C(26) | 1.376(13) | ||||
| O(1)-H(1E) | 0.907(11) | C(9)-C(10) | 1.364(9) | C(25)-H(25A) | 0.9300 | ||||
| O(2)-C(8) | 1.409(7) | C(10)-C(11) | 1.385(12) | C(26)-C(27) | 1.315(12) | ||||
| O(2)-C(7) | 1.418(7) | C(10)-H(10A) | 0.9300 | C(26)-H(26A) | 0.9300 | ||||
| O(3)-C(15) | 1.400(8) | C(11)-C(12) | 1.405(13) | C(27)-C(28) | 1.384(13) | ||||
| O(3)-C(2) | 1.424(6) | C(11)-H(11A) | 0.9300 | C(27)-H(27A) | 0.9300 | ||||
| O(4)-C(22) | 1.390(6) | C(12)-C(13) | 1.377(13) | C(28)-H(28A) | 0.9300 | ||||
| O(4)-C(3) | 1.434(6) | C(12)-H(12A) | 0.9300 | C(29)-C(30) | 1.498(9) | ||||
| O(5)-C(29) | 1.425(8) | C(13)-C(14) | 1.371(11) | C(29)-H(29A) | 0.9700 | ||||
| O(5)-C(4) | 1.446(6) | C(13)-H(13A) | 0.9300 | C(29)-H(29B) | 0.9700 | ||||
| O(6)-C(37) | 1.422(8) | C(14)-H(14A) | 0.9300 | C(30)-C(35) | 1.319(11) | ||||
| O(6)-H(6E) | 0.911(11) | C(15)-C(16) | 1.477(9) | C(30)-C(31) | 1.338(11) | ||||
| O(7)-C(38) | 1.413(8) | C(15)-H(15A) | 0.9700 | C(31)-C(32) | 1.318(13) | ||||
| O(7)-H(7E) | 0.914(11) | C(15)-H(15B) | 0.9700 | C(31)-H(31A) | 0.9300 | ||||
| C(1)-C(7) | 1.529(7) | C(16)-C(17) | 1.376(9) | C(32)-C(33) | 1.374(19) | ||||
| C(1)-C(6) | 1.534(7) | C(16)-C(21) | 1.394(10) | C(32)-H(32A) | 0.9300 | ||||
| C(1)-C(2) | 1.542(7) | C(17)-C(18) | 1.336(12) | C(33)-C(34) | 1.369(19) | ||||
| C(2)-C(3) | 1.517(7) | C(17)-H(17A) | 0.9300 | C(31)-H(33A) | 0.9300 | ||||
| C(2)-H(2A) | 0.9800 | C(18)-C(19) | 1.311(13) | C(34)-C(35) | 1.492(16) | ||||
| C(3)-C(4) | 1.522(8) | C(18)-H(18A) | 0.9300 | C(34)-H(34A) | 0.9300 | ||||
| C(3)-H(3A) | 0.9800 | C(19)-C(20) | 1.351(13) | C(35)-H(35A) | 0.9300 |
| C(4)-C(5) | 1.533(7) | C(19)-H(19A) | 0.9300 | C(36)-C(37) | 1.494(9) |
| C(4)-H(4A) | 0.9800 | C(20)-C(21) | 1.484(13) | C(36)-C(38) | 1.526(9) |
| C(5)-C(6) | 1.531(7) | C(20)-H(20A) | 0.9300 | C(36)-H(36A) | 0.9800 |
| C(5)-H(5A) | 0.9800 | C(21)-H(21A) | 0.9300 | C(37)-H(37A) | 0.9700 |
| C(6)-H(6A) | 0.9700 | C(22)-C(23) | 1.507(9) | C(37)-H(37B) | 0.9700 |
| C(6)-H(6B) | 0.9700 | C(22)-H(22A) | 0.9700 | C(38)-H(38A) | 0.9700 |
| C(7)-H(7A) | 0.9700 | C(22)-H(22B) | 0.9700 | C(38)-H(38B) | 0.9700 |
| C(7)-H(7B) | 0.9700 | C(23)-C(28) | 1.359(10) |
Table 4. bond angle (Bond angles[° (deg)])
| Atom-atom-atom (Atom-atom-atom) | Angle (Angle) | Atom-atom-atom (Atom-atom-atom) | Angle (Angle) |
| C(36)-N(1)-C(5) | 115.9(4) | C(17)-C(16)-C(15) | 120.6(7) |
| C(36)-N(1)-H(1B) | 105(4) | C(21)-C(16)-C(15) | 121.2(7) |
| C(5)-N(1)-H(1B) | 108(4) | C(18)-C(17)-C(16) | 123.6(9) |
| C(1)-O(1)-H(1E) | 108(5) | C(18)-C(17)-H(17A) | 118.2 |
| C(8)-O(2)-C(7) | 113.1(4) | C(16)-C(17)-H(17A) | 118.2 |
| C(15)-O(3)-C(2) | 115.6(5) | C(19)-C(18)-C(17) | 118.7(10) |
| C(22)-O(4)-C(3) | 116.4(4) | C(19)-C(18)-H(18A) | 120.7 |
| C(29)-O(5)-C(4) | 114.3(5) | C(17)-C(18)-H(18A) | 120.7 |
| C(37)-O(6)-H(6E) | 121(5) | C(18)-C(19)-C(20) | 125.7(10) |
| C(38)-O(7)-H(7E) | 112(5) | C(18)-C(19)-H(19A) | 117.2 |
| O(1)-C(1)-C(7) | 105.8(4) | C(20)-C(19)-H(19A) | 117.2 |
| O(1)-C(1)-C(6) | 111.5(4) | C(19)-C(20)-C(21) | 115.7(8) |
| O(7)-C(1)-C(6) | 110.9(4) | C(19)-C(20)-H(20A) | 122.2 |
| O(1)-C(1)-C(2) | 110.7(4) | C(21)-C(20)-H(20A) | 122.2 |
| C(7)-C(1)-C(2) | 111.1(4) | C(16)-C(21)-C(20) | 118.1(8) |
| C(6)-C(1)-C(2) | 107.0(4) | C(16)-C(21)-H(21A) | 120.9 |
| O(3)-C(2)-C(3) | 111.8(4) | C(20)-C(21)-H(21A) | 120.9 |
| O(3)-C(2)-C(1) | 110.6(4) | O(4)-C(22)-C(23) | 110.7(5) |
| C(3)-C(2)-C(1) | 111.4(4) | O(4)-C(22)-H(22A) | 109.5 | ||
| O(3)-C(2)-H(2A) | 107.6 | C(23)-C(22)-H(22A) | 109.5 | ||
| C(3)-C(2)-H(2A) | 107.6 | O(4)-C(22)-H(22B) | 109.5 | ||
| C(1)-C(2)-H(2A) | 107.6 | C(23)-C(22)-H(22B) | 109.5 | ||
| O(4)-C(3)-C(2) | 109.8(4) | H(22A)-C(22)-H(22B) | 108.1 | ||
| O(4)-C(3)-C(4) | 107.6(4) | C(28)-C(23)-C(24) | 118.2(7) | ||
| C(2)-C(3)-C(4) | 110.4(4) | C(28)-C(23)-C(22) | 119.6(7) | ||
| O(4)-C(3)-H(3A) | 109.7 | C(24)-C(23)-C(22) | 122.2(6) | ||
| C(2)-C(3)-H(3A) | 109.7 | C(23)-C(24)-C(25) | 120.7(7) | ||
| C(4)-C(3)-H(3A) | 109.7 | C(23)-C(24)-H(24A) | 119.7 | ||
| O(5)-C(4)-C(3) | 107.0(4) | C(25)-C(24)-H(24A) | 119.7 | ||
| O(5)-C(4)-C(5) | 110.6(4) | C(26)-C(25)-C(24) | 118.8(9) | ||
| C(3)-C(4)-C(5) | 116.4(4) | C(26)-C(25)-H(25A) | 120.6 | ||
| O(5)-C(4)-H(4A) | 107.5 | C(24)-C(25)-H(25A) | 120.6 | ||
| C(3)-C(4)-H(4A) | 107.5 | C(27)-C(26)-C(25) | 120.7(9) | ||
| C(5)-C(4)-H(4A) | 107.5 | C(27)-C(26)-H(26A) | 119.7 | ||
| N(1)-C(5)-C(4) | 110.6(4) | C(25)-C(26)-H(26A) | 119.7 | ||
| N(1)-C(5)-C(6) | 110.4(4) | C(26)-C(27)-C(28) | 120.8(9) | ||
| C(4)-C(5)-C(6) | 110.5(4) | C(26)-C(27)-H(27A) | 119.6 | ||
| N(1)-C(5)-H(5A) | 108.4 | C(28)-C(27)-H(27A) | 119.6 | ||
| C(4)-C(5)-H(5A) | 108.4 | C(23)-C(28)-C(27) | 120.6(9) | ||
| C(6)-C(5)-H(5A) | 108.4 | C(23)-C(28)-H(28A) | 119.7 | ||
| C(1)-C(6)-C(5) | 112.7(4) | C(27)-C(28)-H(28A) | 119.7 | ||
| C(1)-C(6)-H(6A) | 109.0 | O(5)-C(29)-C(30) | 109.6(6) | ||
| C(5)-C(6)-H(6A) | 109.0 | O(5)-C(29)-H(29A) | 109.7 | ||
| C(1)-C(6)-H(6B) | 109.0 | C(30)-C(29)-H(29A) | 109.7 | ||
| C(5)-C(6)-H(6B) | 109.0 | O(5)-C(29)-H(29B) | 109.7 | ||
| H(6A)-C(6)-H(6B) | 107.8 | C(30)-C(29)-H(29B) | 109.7 | ||
| O(2)-C(7)-C(1) | 109.7(4) | H(29A)-C(29)-H(29B) | 108.2 | ||
| O(2)-C(7)-H(7A) | 109.7 | C(35)-C(30)-C(31) | 122.4(8) | ||
| C(1)-C(7)-H(7A) | 109.7 | C(35)-C(30)-C(29) | 118.8(8) | ||
| O(2)-C(7)-H(7B) | 109.7 | C(31)-C(30)-C(29) | 118.6(8) | ||
| C(1)-C(7)-H(7B) | 109.7 | C(32)-C(31)-C(30) | 121.6(12) | ||
| H(7A)-C(7)-H(7B) | 108.2 | C(32)-C(31)-H(31A) | 119.2 | ||
| O(2)-C(8)-C(9) | 109.9(5) | C(30)-C(31)-H(31A) | 119.2 | ||
| O(2)-C(8)-H(8A) | 109.7 | C(31)-C(32)-C(33) | 115.9(13) | ||
| C(9)-C(8)-H(8A) | 109.7 | C(31)-C(32)-H(32A) | 122.0 | ||
| O(2)-C(8)-H(8B) | 109.7 | C(33)-C(32)-H(32A) | 122.0 | ||
| C(9)-C(8)-H(8B) | 109.7 | C(32)-C(33)-C(34) | 129.8(12) | ||
| H(8A)-C(8)-H(8B) | 108.2 | C(32)-C(33)-H(33A) | 115.1 | ||
| C(14)-C(9)-C(10) | 118.8(7) | C(34)-C(33)-H(33A) | 115.1 | ||
| C(14)-C(9)-C(8) | 121.6(6) | C(33)-C(34)-C(35) | 108.0(10) | ||
| C(10)-C(9)-C(8) | 119.7(7) | C(33)-C(34)-H(34A) | 126.0 | ||
| C(9)-C(10)-C(11) | 121.1(8) | C(35)-C(34)-H(34A) | 126.0 | ||
| C(9)-C(10)-H(10A) | 119.4 | C(30)-C(35)-C(34) | 122.1(10) | ||
| C(11)-C(10)-H(10A) | 119.4 | C(30)-C(35)-H(35A) | 119.0 | ||
| C(10)-C(11)-C(12) | 119.6(8) | C(34)-C(35)-H(35A) | 119.0 | ||
| C(10)-C(11)-H(11A) | 120.2 | N(1)-C(36)-C(37) | 107.5(5) | ||
| C(12)-C(11)-H(11A) | 120.2 | N(1)-C(36)-C(38) | 115.8(5) | ||
| C(13)-C(12)-C(11) | 118.4(8) | C(37)-C(36)-C(38) | 110.6(5) | ||
| C(13)-C(12)-H(12A) | 120.8 | N(1)-C(36)-H(36A) | 107.6 | ||
| C(11)-C(12)-H(12A) | 120.8 | C(37)-C(36)-H(36A) | 107.6 | ||
| C(14)-C(13)-C(12) | 120.1(9) | C(38)-C(36)-H(36A) | 107.6 | ||
| C(14)-C(13)-H(13A) | 119.9 | O(6)-C(37)-C(36) | 110.1(6) | ||
| C(12)-C(13)-H(13A) | 119.9 | O(6)-C(37)-H(37A) | 109.6 | ||
| C(9)-C(14)-C(13) | 122.0(7) | C(36)-C(37)-H(37A) | 109.6 | ||
| C(9)-C(14)-H(14A) | 119.0 | O(6)-C(37)-H(37B) | 109.6 | ||
| C(13)-C(14)-H(14A) | 119.0 | C(36)-C(37)-H(37B) | 109.6 | ||
| O(3)-C(15)-C(16) | 113.2(6) | H(37A)-C(37)-H(37B) | 108.2 | ||
| O(3)-C(15)-H(15A) | 108.9 | O(7)-C(38)-C(36) | 112.1(5) | ||
| C(16)-C(15)-H(15A) | 108.9 | O(7)-C(38)-H(38A) | 109.2 |
| O(3)-C(15)-H(15B) | 108.9 | C(36)-C(38)-H(38A) | 109.2 |
| C(16)-C(15)-H(15B) | 108.9 | O(7)-C(38)-H(38B) | 109.2 |
| H(15A)-C(15)-H(15B) | 107.7 | C(36)-C(38)-H(38B) | 109.2 |
| C(17)-C(16)-C(21) | 118.1(7) | H(38A)-C(38)-H(38B) | 107.9 |
Table 5. torsional angle (Torsion angles[° (deg)])
| Atom-atom-atom-atom (Atom-atom-atom-atom) | Angle (Angle) | Atom-atom-atom-atom (Atom-atom-atom-atom) | Angle (Angle) | ||
| C(15)-O(3)-C(2)-C(3) | 93.1(7) | C(10)-C(9)-C(14)-C(13) | 0.3(12) | ||
| C(15)-O(3)-C(2)-C(1) | -142.2(6) | C(8)-C(9)-C(14)-C(13) | 179.9(7) | ||
| O(1)-C(1)-C(2)-O(3) | -66.1(5) | C(12)-C(13)-C(14)-C(9) | -0.5(14) | ||
| C(7)-C(1)-C(2)-O(3) | 51.2(6) | C(2)-O(3)-C(15)-C(16) | 151.8(7) | ||
| C(6)-C(1)-C(2)-O(3) | 172.3(4) | O(3)-C(15)-C(16)-C(17) | -62.6(11) | ||
| O(1)-C(1)-C(2)-C(3) | 58.9(5) | O(3)-C(15)-C(16)-C(21) | 119.3(8) | ||
| C(7)-C(1)-C(2)-C(3) | 176.1(4) | C(21)-C(16)-C(17)-C(18) | 0.2(11) | ||
| C(6)-C(1)-C(2)-C(3) | -62.8(5) | C(15)-C(16)-C(17)-C(18) | -178.0(8) | ||
| C(22)-O(4)-C(3)-C(2) | 127.2(5) | C(16)-C(17)-C(18)-C(19) | 1.8(14) | ||
| C(22)-O(4)-C(3)-C(4) | -112.6(5) | C(17)-C(18)-C(19)-C(20) | -4.2(15) | ||
| O(3)-C(2)-C(3)-O(4) | -60.8(5) | C(18)-C(19)-C(20)-C(21) | 4.0(13) | ||
| C(1)-C(2)-C(3)-O(4) | 175.0(4) | C(17)-C(16)-C(21)-C(20) | -0.3(9) | ||
| O(3)-C(2)-C(3)-C(4) | -179.2(4) | C(15)-C(16)-C(21)-C(20) | 177.9(6) | ||
| C(1)-C(2)-C(3)-C(4) | 56.5(6) | C(19)-C(20)-C(21)-C(16) | -1.7(10) | ||
| C(29)-O(5)-C(4)-C(3) | -159.2(6) | C(3)-O(4)-C(22)-C(23) | 168.8(5) | ||
| C(29)-O(5)-C(4)-C(5) | 73.1(7) | O(4)-C(22)-C(23)-C(28) | -143.2(7) | ||
| O(4)-C(3)-C(4)-O(5) | 67.9(5) | O(4)-C(22)-C(23)-C(24) | 38.7(9) | ||
| C(2)-C(3)-C(4)-O(5) | -172.3(4) | C(28)-C(23)-C(24)-C(25) | 2.6(11) | ||
| O(4)-C(3)-C(4)-C(5) | -167.8(4) | C(22)-C(23)-C(24)-C(25) | -179.3(7) | ||
| C(2)-C(3)-C(4)-C(5) | -48.1(6) | C(23)-C(24)-C(25)-C(26) | -0.4(14) | ||
| C(36)-N(1)-C(5)-C(4) | -162.5(4) | C(24)-C(25)-C(26)-C(27) | -3.4(15) | ||
| C(36)-N(1)-C(5)-C(6) | 74.9(5) | C(25)-C(26)-C(27)-C(28) | 4.8(17) | ||
| O(5)-C(4)-C(5)-N(1) | 45.3(5) | C(24)-C(23)-C(28)-C(27) | -1.3(12) |
| C(3)-C(4)-C(5)-N(1) | -77.1(5) | C(22)-C(23)-C(28)-C(27) | -179.4(8) |
| O(5)-C(4)-C(5)-C(6) | 167.8(4) | C(26)-C(27)-C(28)-C(23) | -2.5(16) |
| C(3)-C(4)-C(5)-C(6) | 45.5(6) | C(4)-O(5)-C(29)-C(30) | 155.2(6) |
| O(1)-C(1)-C(6)-C(5) | -60.5(6) | O(5)-C(29)-C(30)-C(35) | 118.7(8) |
| C(7)-C(1)-C(6)-C(5) | -178.2(5) | O(5)-C(29)-C(30)-C(31) | -66.3(10) |
| C(2)-C(1)-C(6)-C(5) | 60.6(6) | C(35)-C(30)-C(31)-C(32) | -1.1(13) |
| N(1)-C(5)-C(6)-C(1) | 70.7(6) | C(29)-C(30)-C(31)-C(32) | -175.9(8) |
| C(4)-C(5)-C(6)-C(1) | -52.0(6) | C(30)-C(31)-C(32)-C(33) | 2.7(14) |
| C(8)-O(2)-C(7)-C(1) | 171.0(5) | C(31)-C(32)-C(33)-C(34) | -4.8(19) |
| O(1)-C(1)-C(7)-O(2) | -177.2(4) | C(32)-C(33)-C(34)-C(35) | 4.2(18) |
| C(6)-C(1)-C(7)-O(2) | -56.2(6) | C(31)-C(30)-C(35)-C(34) | 0.7(12) |
| C(2)-C(1)-C(7)-O(2) | 62.6(6) | C(29)-C(30)-C(35)-C(34) | 175.5(8) |
| C(7)-O(2)-C(8)-C(9) | -171.9(5) | C(33)-C(34)-C(35)-C(30) | -2.0(14) |
| O(2)-C(8)-C(9)-C(14) | -42.9(9) | C(5)-N(1)-C(36)-C(37) | 170.8(5) |
| O(2)-C(8)-C(9)-C(10) | 136.8(6) | C(5)-N(1)-C(36)-C(38) | 46.7(7) |
| C(14)-C(9)-C(10)-C(11) | -0.2(11) | N(1)-C(36)-C(37)-O(6) | 172.6(6) |
| C(8)-C(9)-C(10)-C(11) | -179.9(7) | C(38)-C(36)-C(37)-O(6) | -60.2(7) |
| C(9)-C(10)-C(11)-C(12) | 0.4(13) | N(1)-C(36)-C(38)-O(7) | 53.3(7) |
| C(10)-C(11)-C(12)-C(13) | -0.6(14) | C(37)-C(36)-C(38)-O(7) | -69.2(7) |
| C(11)-C(12)-C(13)-C(14) | 0.7(14) |
Table 6. hydrogen bond bond distance and bond angle (Hydrogen-bond lengths[
] and angles[° (deg)])
| D-H…A | d(D-H) | d(H…A) | d(D…A) | Angle (angles) (DHA) |
| O(7)-H(7E)…O(1)#1 | 0.914(11) | 1.931(18) | 2.837(5) | 171(8) |
| O(6)-H(6E)…O(7)#2 | 0.911(11) | 1.98(3) | 2.836(7) | 156(6) |
| O(1)-H(1E)…N(1) | 0.907(11) | 1.98(4) | 2.810(6) | 151(7) |
Usually, this crystallization can also characterize by the data of its powder x-ray diffraction, and concrete is that 2 θ are 16.76,18.90 24.00 ± 0.15 ° X-ray diffraction peak can also be 8.24 by 2 θ further, 11.76 23.22,25.88 ± 0.15 ° of X-ray diffraction peak of locating characterizes.
In addition, this crystallization can show thermodynamic characteristics by its DSC, and its fusing point is at 89.7 ℃.
A kind of preparation Tetrabenzyl voglibose crystalline method, concrete steps are: 1 part of buttery Tetrabenzyl voglibose is dissolved in the polar aprotic solvent of 0.5-5 times (volume ratio), preferred 1-3 is doubly; Polar aprotic solvent is selected from ethyl acetate, isopropyl ether, ether, tetrahydrofuran (THF) etc., ethyl acetate, isopropyl ether; Add then in another non-polar solvent of 2-20 times (volume ratio), preferred 2-10 doubly; Non-polar solvent is selected from hexanaphthene, normal hexane, tetracol phenixin, sherwood oil etc., preferred hexanaphthene, normal hexane; Separate out crystallization under stirring at room, placed then 1-5 hour, put 1-5 hour at 0-5 ℃, the colourless granular crystallization vacuum-drying that filters out 10-12 hour just obtains the crystallization of above-mentioned Tetrabenzyl voglibose.
Resulting Tetrabenzyl voglibose crystallization can make highly purified voglibose by further debenzylation reaction.
Positively effect of the present invention is: the Tetrabenzyl voglibose crystal form is compared with oily, and easier storage and transport are taken with weighing more conveniently during use, be convenient to feed intake and production operation.Simultaneously because the Tetrabenzyl voglibose of crystalline state has purity and the content higher than oily usually, thereby when utilizing its preparation voglibose, the impurity of bringing in the reaction or producing still less, can prepare higher-quality voglibose so utilize this crystallization, thereby has better result of treatment, toxic side effect still less after making the voglibose of producing make preparation.
The present invention is further illustrated below in conjunction with drawings and Examples.But embodiment does not constitute any restriction to the present invention.
Description of drawings
Fig. 1 is the operational path for preparing voglibose by Tetrabenzyl voglibose.
Fig. 2 is that the molecule stereographic map that the monocrystalline X-ray diffraction obtains is carried out in the Tetrabenzyl voglibose crystallization.
Fig. 3 is a molecule structure cell accumulation graph in the crystal of Tetrabenzyl voglibose.
Fig. 4 passes through hydrogen bond action power bonded synoptic diagram between the molecule in the Tetrabenzyl voglibose crystalline structure.
Fig. 5 is the x-ray diffraction pattern of Tetrabenzyl voglibose crystalline powder.
Fig. 6 is the differential scanning calorimetric thermogram of Tetrabenzyl voglibose.
Fig. 7 is the infrared spectrogram of Tetrabenzyl voglibose.
Embodiment
Testing conditions:
1, monocrystalline X-ray diffraction
The instrument model: the X-ray image plate AXIS-IV of system type, Japanese company of science produces.
2, powder x-ray diffraction
The used equipment of powder x-ray diffraction is the DMAX-IIIB type of Japanese company of science,
Copper target (X-Ray tube with Cu target anode) is used in the X ray emission,
Divergency (1 ° of Divergence slits) is accepted slit (receiving slit 0.15mm), nephelometric turbidity unit (1 ° of Scatter slit),
Power supply (Power): 35 kilovolts (35KV), 30 milliamperes (30mA)
Sweep velocity (Scanning speed): 4deg/min is (step): 0.02deg at interval.
3, infrared spectra
Infrared spectrometer is the NEXUS-470 of a Nicolet company type, adopts pellet technique to measure.
4, dsc
Differential scanning calorimeter is the DSC204 type of NETZSCH company.
Sample introduction weight: 3mg
Temperature range: 30-200 ℃
Rate of heating: 3 ℃/min
Embodiment 1 buttery (1S)-(1 (hydroxyl), 2,4,5/1,3) amino-2,3,4-three-oxygen-benzyl-5-[(2-hydroxyl-1-(methylol) ethyl)]-1-carbon-benzyloxymethyl-1,2,3,4-hexanaphthene tetrol (is called for short Tetrabenzyl voglibose (as follows), (II)) preparation (reference literature J.Org.Chem.1992,57,3651 methods)
With (1S)-(1 (hydroxyl), 2,4,5/1,3)-2,3,4-three-oxygen-benzyl-1-carbon-benzyloxymethyl-5-oxygen-1,2,3,4-hexanaphthene tetrol (6.0g, 10.8mmol) with 2-amino-1, ammediol (3.0g, 33mmol) be dissolved in the 30ml methyl alcohol, add sodium cyanoborohydride under room temperature (1.5g 24mmol), finishes in batches, continue to stir 16 hours in room temperature, reaction solution is concentrated, remaining with ethyl acetate 300ml dissolving, use the 100ml water washing, again with 1% aqueous hydrochloric acid 100ml washing 2 times, 5% aqueous sodium carbonate 100ml washing 2 times, saturated aqueous common salt 100ml washing 2 times, anhydrous sodium sulfate drying.Reclaim ethyl acetate, remaining silica gel (150ml) column chromatography of using is used eluent ethyl acetate, concentrates ethyl acetate, obtains lurid oily matter 5.2g.(the HPLC method is measured content: 89.4%)
The preparation of embodiment 2 Tetrabenzyl vogliboses (II) crystalline
Buttery Tetrabenzyl voglibose 1.0g is dissolved in the 2.5ml ethyl acetate, stir and add hexanaphthene 6ml down, solution was at room temperature stirred 1.5 hours, generate colourless granular crystallization, continuation was placed 5 hours in room temperature, and then placed filtration 5 hours in 0-5 ℃, crystallization vacuum-drying at room temperature 10 hours obtains colourless crystalline particulate 0.76g.The HPLC method is measured content: 98.5%; Mp88.2-90.8 ℃; [α]
22 D+ 30.8 ° (cl, chloroform);
1H NMR (CDCl
3, 500Hz), δ: 1.63 (1H, dd, J=2.8,15.1Hz), 1.91 (1H, dd, J=2.9,15.1Hz), 2.78 (1H, m), 3.19 (1H, d, J=8.6Hz), 3.39 (1H, m), 3.54 (1H, d, J=8.6Hz), 3.62-3.73 (6H, m), 4.13 (1H, t, J=9.6Hz), 4.39 (2H, s), 4.59 (1H, d, J=11.1), 4.64 (1H, d, J=11.4), 4.72 (1H, d, J=11.4), 4.82 (1H, d, J=10.6), 4.91 (1H, d, J=11.2), 4.93 (1H, d, J=10.7), 7.24-7.35 (20H, m)
The preparation of embodiment 3 Tetrabenzyl vogliboses (II) crystalline
Buttery Tetrabenzyl voglibose 3.0g is dissolved in the 10ml isopropyl ether, stir and add normal hexane 25ml down, solution was at room temperature stirred 1 hour, generate colourless granular crystallization, continuation was placed 1 hour in room temperature, and then placed filtration 3 hours in 0-5 ℃, crystallization vacuum-drying at room temperature 12 hours obtains colourless granular crystallization 2.5g.The HPLC method is measured content: 98.7%; Mp88.5-90.7 ℃; [α]
22 D+ 30.6 ° (cl, chloroform), hydrogen spectrum data are with the unanimity of embodiment 2.
The preparation of embodiment 4 Tetrabenzyl vogliboses (II) crystalline
Buttery Tetrabenzyl voglibose 3.0g is dissolved in the 1.5ml ether, stir and add sherwood oil 6ml down, solution was at room temperature stirred 1 hour, generate colourless granular crystallization, continuation was placed 3 hours in room temperature, and then placed filtration 5 hours in 0-5 ℃, crystallization vacuum-drying at room temperature 11 hours obtains colourless crystalline particulate 2.3g.The HPLC method is measured content: 98.5%; Mp88.1-90.6 ℃; [α]
22 D+ 30.5 ° (cl, chloroform), hydrogen spectrum data are with the unanimity of embodiment 2.
The preparation of embodiment 5 Tetrabenzyl vogliboses (II) crystalline
Buttery Tetrabenzyl voglibose 2.0g is dissolved in the 10ml tetrahydrofuran (THF), stir and add tetracol phenixin 40ml down, solution was at room temperature stirred 1 hour, generate colourless granular crystallization, continuation was placed 5 hours in room temperature, and then placed filtration 1 hour in 0-5 ℃, crystallization vacuum-drying at room temperature 12 hours obtains colourless crystalline particulate 1.2g.HPLC measures content: 98.6%; Mp88.0-90.5 ℃; [α]
22 D+ 30.7 ° (cl, chloroform), hydrogen spectrum data are with the unanimity of embodiment 2.
Embodiment 6 (1S)-(1 (hydroxyl), 2,4,5/1,3)-5-[(2-hydroxyl-1-(methylol) ethyl) amino]-1-carbon-methylol-1,2,3, the preparation of 4-hexanaphthene tetrol (voglibose, (I))
With the Tetrabenzyl voglibose crystallization of above-mentioned preparation (3.0g, 4.8mmol) be dissolved in 90% formic acid/methyl alcohol (1: 19,60ml) in; add palladium black (0.6g), under nitrogen protection,, filter in room temperature reaction 12 hours; wash with methanol (1: 1) 20ml; filtrate concentrates, and is remaining with strong-acid ion exchange resin (250ml) absorption, water washing; use 0.5N ammoniacal liquor wash-out then; after elutriant concentrates, add dehydrated alcohol 50ml, boil; cooling slightly; add gac, continue heating 10 minutes, filter; filtrate naturally cools to room temperature; separate out white crystals, continue to place 3 hours, filter at 0-5 ℃; a small amount of absolute ethanol washing; vacuum-drying 12 hours obtains white crystals 1.1g, mp:164-166 ℃.The structural identification spectroscopic data is consistent with bibliographical information.
Claims (9)
1. the Tetrabenzyl voglibose of a crystallized form, its chemistry (1S)-(1 (hydroxyl), 2,4 by name, 5/1,3) amino-2,3,4-three-oxygen-benzyl-5-[(2-hydroxyl-1-(methylol) ethyl)]-1-carbon-benzyloxymethyl-1,2,3,4-hexanaphthene tetrol, structural formula is as follows:
It is characterized by:
X-ray diffraction pattern with Tetrabenzyl voglibose crystalline powder shown in Figure 5;
Has differential scanning calorimetric thermogram shown in Figure 6;
Has infrared spectrogram feature shown in Figure 7.
2. the preparation method of the Tetrabenzyl voglibose of crystallized form according to claim 1, its key step is: 1 part of buttery Tetrabenzyl voglibose is dissolved in the polar aprotic solvent of 0.5-5 times of volume ratio; Add another non-polar solvent of 2-20 times of volume ratio then, under stirring at room, separate out crystallization, placed then 1-5 hour, placed the crystallization vacuum-drying that filters out 10-12 hour 1-5 hour at 0-5 ℃ again.
3. according to the preparation method of claim 2, it is characterized in that: described polar aprotic solvent is a kind of in ethyl acetate, isopropyl ether, ether, the tetrahydrofuran (THF).
4. according to the preparation method of claim 3, it is characterized in that: described polar aprotic solvent is an ethyl acetate.
5. according to the preparation method of claim 3, it is characterized in that: described polar aprotic solvent is an isopropyl ether.
6. according to the preparation method of claim 2, it is characterized in that: described non-polar solvent is hexanaphthene, normal hexane, tetracol phenixin or sherwood oil.
7. according to the preparation method of claim 6, it is characterized in that: described non-polar solvent is a hexanaphthene.
8. according to the preparation method of claim 6, it is characterized in that: described non-polar solvent is a normal hexane.
9. the Tetrabenzyl voglibose of crystallized form according to claim 1 is in the application of preparation voglibose.
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| JP4408340B2 (en) * | 2002-03-22 | 2010-02-03 | 武田薬品工業株式会社 | Fast disintegrating solid preparation |
| WO2005049547A1 (en) | 2003-11-21 | 2005-06-02 | Ranbaxy Laboratories Limited | Process for the preparation of 1,2,3,4-cyclohexanetetrol derivatives |
| CN100393694C (en) * | 2006-07-17 | 2008-06-11 | 深圳市药兴生物科技开发有限公司 | Tetrabenzyl voglibose crystallizing and preparing process |
-
2006
- 2006-07-17 CN CNB2006100617134A patent/CN100393694C/en not_active Expired - Fee Related
-
2007
- 2007-06-18 KR KR1020087031619A patent/KR101379988B1/en not_active IP Right Cessation
- 2007-06-18 JP JP2009519780A patent/JP5216006B2/en not_active Expired - Fee Related
- 2007-06-18 WO PCT/CN2007/001902 patent/WO2008011791A1/en active Application Filing
- 2007-06-18 CA CA002654424A patent/CA2654424A1/en not_active Abandoned
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005030698A1 (en) * | 2003-09-26 | 2005-04-07 | Ranbaxy Laboratories Limited | Process for the preparation of voglibose |
| WO2005049574A1 (en) * | 2003-11-20 | 2005-06-02 | Warner-Lambert Company Llc | Androgen receptor modulators |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2008011791A1 (en) | 2008-01-31 |
| CN1931826A (en) | 2007-03-21 |
| KR101379988B1 (en) | 2014-04-01 |
| CA2654424A1 (en) | 2008-01-31 |
| JP5216006B2 (en) | 2013-06-19 |
| KR20090031376A (en) | 2009-03-25 |
| JP2009543814A (en) | 2009-12-10 |
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