2-Methylene-19-nor-20(S)-1alpha-hydroxy-bis-homo-pregnacalciferol in crystalline form

BACKGROUND OF THE INVENTION

[0002] The present invention relates to purification of organic compounds, and more particularly to the purification of 2-methylene-19-nor-20(S)-1α-hydroxy-bis-homo-pregnacalciferol (referred to herein as 2MBP and/or 2-MbisP) by preparing it in crystalline form.

[0003] Purification of organic compounds, especially those designated for pharmaceutical use, is of considerable importance for chemists synthesizing such compounds. Preparation of the compound usually requires many synthetic steps and, therefore, the final product can be contaminated not only with side-products derived from the last synthetic step of the procedure but also with compounds that were formed in previous steps. Even chromatographic purification, which is a very efficient but relatively time-consuming process, does not usually provide compounds which are sufficiently pure to be used as drugs.

[0004] Depending on the method used to synthesize 1α-hydroxyvitamin D compounds, different minor undesirable compounds can accompany the final product. Thus, for example, if direct C-1 hydroxylation of 5,6-trans geometric isomer of vitamin D is performed, followed by SeO2/NMO oxidation and photochemical irradiation [see Andrews et al., J. Org. Chem. 51, 1635 (1986); Calverley et al., Tetrahedron 43, 4609 (1987); Choudry et al., J. Org. Chem. 58, 1496 (1993)], the final 1α-hydroxyvitamin D product can be contaminated with 1β-hydroxy- as well as 5,6-trans isomers. If the method consists of C-1 allylic oxidation of the 4-phenyl-1,2,4-triazoline-3,5-dione adduct of the previtamin D compound, followed by cycloreversion of the modified adduct under basic conditions [Nevinckx et al., Tetrahedron 47, 9419 (1991); Vanmaele et al., Tetrahedron 41, 141 (1985) and 40, 1179 (1991); Vanmaele et al., Tetrahedron Lett. 23, 995 (1982)], one can expect that the desired 1α-hydroxyvitamin can be contaminated with the previtamin 5(10),6,8-triene and 1β-hydroxy isomer. One of the most useful C-1 hydroxylation methods, of very broad scope and numerous applications, is the experimentally simple procedure elaborated by Paaren et al. [see J. Org. Chem. 45, 3253 (1980) and Proc. Natl. Acad. Sci. U.S.A. 75, 2080 (1978)]. This method consists of allylic oxidation of 3,5-cyclovitamin D derivatives, readily obtained from the buffered solvolysis of vitamin D tosylates, with SeO2/t-BuOOH and subsequent acid-catalyzed cycloreversion to the desired 1α-hydroxy compounds. Taking into account this synthetic path it is reasonable to assume that the final product can be contaminated with 1α-hydroxy epimer, 5,6-trans isomer and the previtamin D form. 1α-hydroxyvitamin D4 is another undesirable contaminant found in 1α-hydroxyvitamin D compounds synthesized from vitamin D2 or from ergosterol. 1α-hydroxyvitamin D4 results from C-1 oxidation of vitamin D4, which in turn is derived from contamination of the commercial ergosterol material. Typically, the final product may contain up to about 1.5% by weight 1α-hydroxyvitamin D4. Thus, a purification technique that would eliminate or substantially reduce the amount of 1α-hydroxyvitamin D4 in the final product to less than about 01.-0.2% would be highly desirable.

[0005] The vitamin D conjugated triene system is not only heat- and light-sensitive but it is also prone to oxidation, leading to the complex mixture of very polar compounds. Oxidation usually happens when a vitamin D compound has been stored for a prolonged time. Other types of processes that can lead to a partial decomposition of vitamin D compounds consist of the some water-elimination reactions; their driving force is allylic (1α) and homoallylic (3β-) position of the hydroxy groups. The presence of such above-mentioned oxidation and elimination products can be easily detected by thin-layer chromatography. Thus, for example, using precoated aluminum silica sheets [with UV indicator; from EM Science (Cherry Hill, N.J.)] and solvent system hexane-ethyl acetate (4:6), the spot of 1α-OH-D2 (Rf 0.27) and its elimination products (Rf's ca. 0.7-0.9) are visible in ultraviolet light. Also, after spraying with sulfuric acid and heating, an additional spot can be visualized (Rf 0), derived from oxidation products.

[0006] Usually, all 1α-hydroxylation procedures require at least one chromatographic purification. However, even chromatographically purified 1α-hydroxyvitamin D compounds, although showing consistent spectroscopic data, suggesting homogeneity, does not meet the purity criteria required for therapeutic agents that can be orally, parenterally or transdermally administered. Therefore, it was evident that a suitable method of purification of 2MBP is required.

SUMMARY OF THE INVENTION

[0007] The present invention relates to a method of purifying 2MBP by means of crystallization to obtain 2MBP in crystalline form. The solvent plays a crucial role in the crystallization process, and is typically an individual liquid substance or a suitable mixture of different liquids. For crystallizing 2MBP, the most appropriate solvent and/or solvent system is characterized by the following factors:

[0008] (1) low toxicity;

[0009] (2) low boiling point;

[0010] (3) significant dependence of solubility properties with regard to temperature (condition necessary for providing satisfactory crystallization yield); and

[0011] (4) relatively low cost.

[0012] It was found that highly apolar solvents (e.g. hydrocarbons) were not suitable due to the low solubility of 2MBP in them. Quite the reverse situation occurred in highly polar solvent media (e.g. alcohols), in which 2MBP showed too high solubility. Therefore, it was concluded that for the successful crystallization of 2MBP, a solvent of medium polarity is required. Interestingly, hexane, so frequently used for crystallization purposes, was found less suitable for crystallization of 2MBP. However, it was found that an individual solvent, namely acetone, was most useful for the crystallization of 2MBP. In addition, it is believed that solvent systems utilizing ethyl acetate, or isopropanol, or chloroform, or dichloromethane, or diethyl ether would also perform well. These solvents are all very easy to remove by evaporation or other well known methods. In all cases the crystallization process occurred easily and efficiently; and the precipitated crystals were sufficiently large to assure their recovery by filtration.

BRIEF DESCRIPTION OF THE DRAWINGS

[0013]
FIG. 1 is an illustration of the three dimensional structure of 2MBD as defined by the atomic positional parameters discovered and set forth herein.

DETAILED DESCRIPTION OF THE INVENTION

[0014] The present invention provides 2-methylene-19-nor-20(S)-1α-hydroxy-bis-homo-pregnacalciferol (2MBP) in crystalline form, a pharmacologically important compound, characterized by the formula shown below:

[0015] The present invention also provides a valuable method of purification of 2MBP. The purification technique involves obtaining the 2MBP product in crystalline form by utilizing a crystallization procedure wherein the 2MBP material to be purified is dissolved using as the solvent a single solvent system comprised of acetone, ethyl acetate, isopropanol, chloroform, dichloromethane, or diethyl ether. The preferred solvent is acetone. Thereafter, the solvent can be removed by evaporation, with or without vacuum, or other means as is well known. The technique can be used to purify a wide range of final products containing 2MBP obtained from any known synthesis thereof, and in varying concentrations, i.e. from microgram amounts to kilogram amounts. As is well known to those skilled in this art, the amount of solvent utilized should be minimized and/or adjusted according to the amount of 2MBP to be purified.

[0016] The usefulness and advantages of the present crystallization procedures is shown in the following specific Examples 1 and 2. After crystallization, the precipitated material was observed under a microscope to confirm its crystalline form. Additionally, X-ray diffraction analysis was performed. Yields of crystallizations were high and the obtained crystals showed a relatively sharp melting point of 162-164° C.

[0017] The described crystallization process of the synthetic 2MBP product represents a valuable purification method, which can remove not only some side products derived from the synthetic path, but, moreover, concomitant 1α-hydroxyvitamin D4. Such impurity is the result of the contamination of natural ergosterol with its 22,23-dihydro analog.

CRYSTALLIZATION OF 2MBP

EXAMPLE 1

Crystallization From Acetone

[0018] (a) 2MBP product to be purified may be dissolved in boiling acetone (1.2 mL, Aldrich) under argon atmosphere, left at room temperature (68° F.) for a few hours (1-3 hrs) and then in a refrigerator (35-45° F.) overnight (8-12 hrs). The precipitated crystals should be filtered off, washed with a small volume of a cold (0° C.) acetone and dried.

[0019] (b) These crystals of 2MBP may then be recrystallized with acetone (0.5 mL) as described in Example 1(a). The precipitated crystals have a relatively sharp melting point of 162-164° C., and were observed under a microscope to confirm their crystalline form.

EXAMPLE 2

Experimental

[0020] A colorless plate-shaped crystal of dimensions 0.40×0.25×0.03 mm was utilized for the structural analysis. Intensity data were collected with a Siemens HISTAR area detector mounted on a platform goniometer using Cu Kα radiation (λ=1.54178 Å) focused with Goebel optics. The crystal was mounted on a thin nylon fiber with vacuum grease and data were collected at ambient temperature, 293° K. The intensity data were measured as a series of ω oscillation frames each of 0.25°; these were comprised of 5 scans (500 images each, 40 sec./image) at detector 2θ of −85° and 2 scans (500 images each, 20 sec./image) at detector 2Θ of −40°. The detector was operated in 512×512 mode and was positioned 6.0 cm from the sample. Coverage of unique data was 95.4% complete to 58.88 degrees in θ. The first 50 frames were repeated at the end of data collection and showed essentially no decay of the crystal diffraction during the data collection. A total of 6917 data was measured in the range 4.38<θ58.88°. The data were merged and scaled to form a set of 2697 independent data with R(int)=0.0562 using SAINT (Bruker-AXS, Inc.).

[0021] The orthorhombic space group P2(1)2(1)2(1) was determined by systematic absences and statistical tests and verified by subsequent refinement. The structure was solved by direct methods and refined by full-matrix least-squares methods on F2 using SHELXL-97 (G. M. Sheldrick, 1994; SHELXTL Version 5 Reference Manual, Bruker-AXS, Inc.). Hydrogen atom positions were intially located in Fourier difference maps, but refined by a riding model with idealized geometries. Non-hydrogen atoms were refined with anisotropic displacement parameters. A total of 229 parameters were refined against 0 restraints and 2697 data to give wR(F2)=0.1369 and S=1.088 for weights of w=I/[s2(F2)+(0.0824 P)2], where P=[Fo2+2Fc2]/3. The final R(F) was 0.0544 for the 2697 observed, [F>2s(F)], data. The final difference map had maxima and minima of 0.126 and −0.153 e/Å3, respectively.

[0022] The three dimensional structure of 2MBP as defined by the following physical data and atomic positional parameters described and calculated herein is illustrated in FIG. 1.

1TABLE 1Crystal data and structure refinement for 2-MbisP.Empirical formulaC23 H36 O2Formula weight344.52Temperature293(2) KWavelength1.54178 ÅCrystal system, space groupOrthorhombic, P2(1)2(1)2(1)Unit cell dimensionsa = 6.6320(13) Å α = 90°b = 15.514(3) Å β = 90°c = 20.194(4) Å γ = 90°Volume2077.7(7) Å3Z, Calculated density4, 1.101 Mg/m3Absorption coefficient0.520 mm−1F(000)760Crystal size0.40 × 0.25 × 0.03 mmTheta range for data collection4.38 to 58.88°Limiting indices−7 <= h <= 5, −12 <= k <= 17,−22 <= 1 <= 21Reflections collected/unique6917/2697 [Rint = 0.0562]Completeness to theta = 25.0095.4%Refinement methodFull-matrix least-squares on F2Data/restraints/parameters2697/0/229Goodness-of-fit on F21.088Final R indices [I > 2sigma(I)]R1 = 0.0544, wR2 = 0.1369R indices (all data)R1 = 0.0622, wR2 = 0.1453Largest diff. peak and hole0.126 and −0.153 e/A−3

[0023]

2

TABLE 2

Atomic coordinates (× 104) and equivalent isotropic

displacement parameters (Å2 × 103)

for 2-MbisP. U(eq) is defined as one third of the trace of

the orthogonalized Uij tensor.

x
y
z
U(eq)

O(1)
1842(3)
3525(1)
5011(1)
62(1)

O(3)
7954(4)
3113(1)
4476(2)
78(1)

C(1)
3883(5)
3729(2)
4852(2)
50(1)

C(2)
4569(5)
3359(2)
4201(2)
58(1)

C(3)
6698(5)
3569(2)
4030(2)
61(1)

C(4)
7074(6)
4537(2)
4057(2)
59(1)

C(5)
6301(5)
4937(2)
4686(2)
48(1)

C(6)
7497(5)
5433(2)
5059(2)
52(1)

C(7)
7012(5)
5872(2)
5673(2)
53(1)

C(8)
8248(5)
6371(2)
6020(2)
50(1)

C(9)
10390(5)
6589(2)
5828(2)
65(1)

C(10)
4161(5)
4704(2)
4851(2)
51(1)

C(11)
10739(6)
7562(2)
5809(2)
70(1)

C(12)
10108(6)
8006(2)
6452(2)
61(1)

C(13)
7933(5)
7806(2)
6640(1)
47(1)

C(14)
7696(5)
6814(2)
6661(2)
50(1)

C(15)
5663(6)
6668(2)
6982(2)
62(1)

C(16)
5453(5)
7416(2)
7474(2)
59(1)

C(17)
7251(5)
8038(2)
7353(2)
51(1)

C(18)
6466(6)
8205(2)
6135(2)
64(1)

C(19)
3405(7)
2898(3)
3811(2)
97(2)

C(20)
6703(6)
8967(2)
7542(2)
65(1)

C(21)
6012(8)
9017(3)
8269(2)
92(2)

C(22)
8368(7)
9636(2)
7418(2)
89(1)

C(23)
10284(9)
9512(3)
7809(3)
116(2)

[0024]

3

TABLE 3

Bond lengths [Å] and angles [°] for 2-MbisP.

O(1)-C(1)
1.426(4)
O(3)-C(3)
1.416(4)

C(1)-C(2)
1.505(5)
C(1)-C(10)
1.524(4)

C(2)-C(19)
1.314(5)
C(2)-C(3)
1.490(5)

C(3)-C(4)
1.522(4)
C(4)-C(5)
1.504(5)

C(5)-C(6)
1.335(4)
C(5)-C(10)
1.502(5)

C(6)-C(7)
1.452(4)
C(7)-C(8)
1.327(4)

C(8)-C(9)
1.511(5)
C(8)-C(14)
1.511(4)

C(9)-C(11)
1.527(5)
C(11)-C(12)
1.530(5)

C(12)-C(13)
1.523(5)
C(13)-C(18)
1.539(5)

C(13)-C(14)
1.548(4)
C(13)-C(17)
1.553(4)

C(14)-C(15)
1.513(5)
C(15)-C(16)
1.534(5)

C(16)-C(17)
1.553(5)
C(17)-C(20)
1.535(5)

C(20)-C(22)
1.536(6)
C(20)-C(21)
1.540(5)

C(22)-C(23)
1.508(7)

O(1)-C(1)-C(2)
113.5(2)
O(1)-C(1)-C(10)
109.6(2)

C(2)-C(1)-C(10)
109.9(3)
C(19)-C(2)-C(3)
122.5(3)

C(19)-C(2)-C(1)
123.6(3)
C(3)-C(2)-C(1)
113.9(3)

O(3)-C(3)-C(2)
107.5(3)
O(3)-C(3)-C(4)
111.9(3)

C(2)-C(3)-C(4)
111.3(3)
C(5)-C(4)-C(3)
112.5(3)

C(6)-C(5)-C(10)
125.1(3)
C(6)-C(5)-C(4)
120.7(3)

C(10)-C(5)-C(4)
114.2(3)
C(5)-C(6)-C(7)
128.3(3)

C(8)-C(7)-C(6)
126.0(3)
C(7)-C(8)-C(9)
125.1(3)

C(7)-C(8)-C(14)
124.6(3)
C(9)-C(8)-C(14)
110.3(3)

C(8)-C(9)-C(11)
111.7(3)
C(5)-C(10)-C(1)
110.8(2)

C(9)-C(11)-C(12)
112.5(3)
C(13)-C(12)-C(11)
112.2(3)

C(12)-C(13)-C(18)
110.6(3)
C(12)-C(13)-C(14)
107.8(3)

C(18)-C(13)-C(14)
110.8(3)
C(12)-C(13)-C(17)
117.3(3)

C(18)-C(13)-C(17)
109.7(3)
C(14)-C(13)-C(17)
100.1(2)

C(15)-C(14)-C(8)
121.0(3)
C(15)-C(14)-C(13)
104.6(3)

C(8)-C(14)-C(13)
113.8(2)
C(14)-C(15)-C(16)
104.2(3)

C(15)-C(16)-C(17)
107.4(3)
C(20)-C(17)-C(16)
111.3(3)

C(20)-C(17)-C(13)
121.2(3)
C(16)-C(17)-C(13)
103.0(2)

C(22)-C(20)-C(17)
115.0(3)
C(22)-C(20)-C(21)
1.09.6(3)

C(17)-C(20)-C(21)
110.8(3)
C(23)-C(22)-C(20)
115.7(4)

[0025]

4

TABLE 4

Anisotropic displacement parameters (Å2 × 103) for 2-MbisP.

The anisotropic displacement factor exponent takes the form:

−2π2[h2 a*2 U11 + . . . + 2 h k a* b* U12]

U11
U22
U33
U23
U13
U12

O(1)
36(1)
59(1)
92(2)
−7(1)
−3(1)
−5(1)

O(3)
42(1)
48(1)
145(2)
3(1)
−17(2)
2(1)

C(1)
34(2)
45(2)
70(2)
−5(2)
−11(2)
−1(1)

C(2)
39(2)
51(2)
83(2)
−21(2)
−14(2)
6(1)

C(3)
55(2)
52(2)
75(2)
−19(2)
−7(2)
8(2)

C(4)
60(2)
56(2)
61(2)
−2(2)
2(2)
0(2)

C(5)
52(2)
34(1)
58(2)
3(1)
−5(2)
1(1)

C(6)
51(2)
45(2)
61(2)
2(1)
5(2)
−9(2)

C(7)
56(2)
42(2)
62(2)
2(1)
6(2)
−8(2)

C(8)
47(2)
44(2)
58(2)
3(1)
−1(2)
−10(2)

C(9)
48(2)
75(2)
73(2)
−15(2)
3(2)
−12(2)

C(10)
44(2)
41(2)
66(2)
−11(1)
−6(2)
4(1)

C(11)
59(2)
78(2)
72(2)
−12(2)
11(2)
−32(2)

C(12)
59(2)
61(2)
63(2)
−5(2)
1(2)
−22(2)

C(13)
43(2)
51(2)
47(2)
5(1)
−6(2)
−7(2)

C(14)
45(2)
52(2)
53(2)
4(1)
−4(2)
−8(2)

C(15)
53(2)
64(2)
69(2)
1(2)
9(2)
−19(2)

C(16)
48(2)
71(2)
58(2)
3(2)
4(2)
0(2)

C(17)
49(2)
53(2)
50(2)
1(1)
−7(2)
−1(2)

C(18)
71(3)
66(2)
57(2)
10(2)
−11(2)
−5(2)

C(19)
53(3)
122(4)
117(3)
−68(3)
−9(3)
−8(2)

C(20)
73(3)
59(2)
64(2)
−5(2)
−2(2)
8(2)

C(21)
117(4)
82(3)
76(2)
−16(2)
20(3)
9(3)

C(22)
104(4)
63(2)
99(3)
−12(2)
18(3)
−6(2)

C(23)
107(4)
101(4)
140(5)
−39(3)
−4(4)
−25(3)

[0026]

5

TABLE 5

Hydrogen coordinates (× 104) and isotropic displacement

parameters (Å2 × 103) for 2-MbisP.

x
y
z
U(eq)

H(1O)
2030
2820
5188
75

H(3O)
9248
3381
4573
94

H(1)
4744
3489
5201
60

H(3)
6972
3366
3580
73

H(4A)
8510
4644
4021
71

H(4B)
6418
4808
3682
71

H(6)
8807
5506
4904
63

H(7)
5716
5796
5840
64

H(9A)
10678
6347
5395
78

H(9B)
11311
6330
6144
78

H(10A)
3261
4960
4528
61

H(10B)
3817
4933
5284
61

H(11A)
9979
7806
5444
84

H(11B)
12157
7673
5728
84

H(12A)
10992
7820
6807
74

H(12B)
10264
8624
6403
74

H(14)
8690
6614
6986
60

H(15A)
5627
6117
7210
74

H(15B)
4592
6682
6655
74

H(16A)
5482
7201
7925
71

H(16B)
4186
7714
7405
71

H(17)
8337
7857
7652
61

H(18A)
6780
8804
6077
97

H(18B)
5109
8148
6295
97

H(18C)
6593
7911
5719
97

H(19A)
3904
2689
3412
117

H(19B)
2083
2780
3935
117

H(20)
5547
9133
7268
78

H(21A)
7037
8779
8551
138

H(21B)
4785
8697
8323
138

H(21C)
5783
9609
8388
138

H(22A)
8703
9627
6950
106

H(22B)
7832
10203
7518
106

H(23A)
9974
9502
8273
174

H(23B)
11194
9978
7717
174

H(23C)
10902
8976
7684
174

[0027]

6

TABLE 6

Torsion angles [°] for 2-MbisP.

O(1)-C(1)-C(2)-C(19)
0.5(5)
C(10)-C(1)-C(2)-C(19)
−122.6(4)

O(1)-C(1)-C(2)-C(3)
179.9(3)
C(10)-C(1)-C(2)-C(3)
56.8(3)

C(19)-C(2)-C(3)-O(3)
−111.3(4)
C(1)-C(2)-C(3)-O(3)
69.2(3)

C(19)-C(2)-C(3)-C(4)
125.8(4)
C(1)-C(2)-C(3)-C(4)
−53.7(4)

O(3)-C(3)-C(4)-C(5)
−71.4(4)
C(2)-C(3)-C(4)-C(5)
48.9(4)

C(3)-C(4)-C(5)-C(6)
128.0(3)
C(3)-C(4)-C(5)-C(10)
−50.1(4)

C(10)-C(5)-C(6)-C(7)
−2.4(5)
C(4)-C(5)-C(6)-C(7)
179.7(3)

C(5)-C(6)-C(7)-C(8)
−178.8(3)
C(6)-C(7)-C(8)-C(9)
1.4(5)

C(6)-C(7)-C(8)-C(14)
−179.6(3)
C(7)-C(8)-C(9)-C(11)
125.7(3)

C(14)-C(8)-C(9)-C(11)
−53.4(4)
C(6)-C(5)-C(10)-C(1)
−125.0(3)

C(4)-C(5)-C(10)-C(1)
53.1(3)
O(1)-C(1)-C(10)-C(5)
179.9(2)

C(2)-C(1)-C(10)-C(5)
−54.7(3)
C(8)-C(9)-C(11)-C(12)
53.0(4)

C(9)-C(11)-C(12)-
−54.6(4)
C(11)-C(12)-C(13)-C(18)
−66.8(4)

C(13)

C(11)-C(12)-C(13)-
54.5(4)
C(11)-C(12)-C(13)-C(17)
166.4(3)

C(14)

C(7)-C(8)-C(14)-C(15)
3.9(5)
C(9)-C(8)-C(14)-C(15)
−177.0(3)

C(7)-C(8)-C(14)-C(13)
−122.0(3)
C(9)-C(8)-C(14)-C(13)
57.2(4)

C(12)-C(13)-C(14)-
168.8(3)
C(18)-C(13)-C(14)-C(15)
−70.1(3)

C(15)

C(17)-C(13)-C(14)-
45.6(3)
C(12)-C(13)-C(14)-C(8)
−57.1(3)

C(15)

C(18)-C(13)-C(14)-
64.1(4)
C(17)-C(13)-C(14)-C(8)
179.7(3)

C(8)

C(8)-C(14)-C(15)-
−163.1(3)
C(13)-C(14)-C(15)-C(16)
−33.1(3)

C(16)

C(14)-C(15)-C(16)-
7.4(4)
C(15)-C(16)-C(17)-C(20)
151.9(3)

C(17)

C(15)-C(16)-C(17)-
20.6(3)
C(12)-C(13)-C(17)-C(20)
79.2(4)

C(13)

C(18)-C(13)-C(17)-
−48.2(4)
C(14)-C(13)-C(17)-C(20)
−164.7(3)

C(20)

C(12)-C(13)-C(17)-
−155.7(3)
C(18)-C(13)-C(17)-C(16)
76.9(3)

C(16)

C(14)-C(13)-C(17)-
−39.5(3)
C(16)-C(17)-C(20)-C(22)
−178.0(3)

C(16)

C(13)-C(17)-C(20)-
−56.8(5)
C(16)-C(17)-C(20)-C(21)
56.9(4)

C(22)

C(13)-C(17)-C(20)-
178.1(3)
C(17)-C(20)-C(22)-C(23)
−62.9(5)

C(21)

C(21)-C(20)-C(22)-
62.8(5)

C(23)

[0028]

7

TABLE 7

Observed and calculated structure factors for 2-MbisP.

h
k
l
10Fo
10Fc
10s
h
k
l
10Fo
10Fc
10s
h
k
l
10Fo
10Fc
10s
h
k
l
10Fo
10Fc
10s
h
k
l
10Fo
10Fc
10s

4
0
0
51
50
3
1
15
0
43
53
3
0
6
1
298
328
8
−4
14
1
38
35
5
1
5
2
153
145
7

6
0
0
48
54
4
2
15
0
82
87
2
1
6
1
326
324
4
−3
14
1
54
53
3
2
5
2
175
176
2

1
1
0
108
125
1
3
15
0
53
49
3
2
6
1
62
70
2
−2
14
1
95
101
3
3
5
2
156
167
5

2
1
0
813
823
10
0
16
0
28
24
8
3
6
1
76
73
2
−1
14
1
78
78
2
4
5
2
194
188
2

4
1
0
448
435
4
1
16
0
25
18
5
4
6
1
68
62
1
0
14
1
73
68
1
5
5
2
99
96
2

5
1
0
62
62
1
2
16
0
17
12
8
5
6
1
125
129
2
1
14
1
78
79
1
6
5
2
84
79
3

6
1
0
65
72
2
1
17
0
54
37
10
6
6
1
89
91
2
2
14
1
97
101
2
7
5
2
70
47
4

0
2
0
650
820
8
1
0
1
304
297
5
−5
7
1
152
158
5
3
14
1
44
53
5
−6
6
2
65
66
3

1
2
0
510
519
6
2
0
1
86
79
1
−4
7
1
168
165
1
4
14
1
44
34
5
−5
6
2
60
66
2

2
2
0
88
88
2
4
0
1
115
107
1
−3
7
1
138
136
2
−3
15
1
33
5
5
−4
6
2
74
77
1

4
2
0
217
213
2
5
0
1
111
115
2
−2
7
1
101
94
2
−2
15
1
46
46
6
−3
6
2
130
128
3

5
2
0
120
117
1
6
0
1
36
28
4
−1
7
1
219
219
3
−1
15
1
25
30
6
−2
6
2
150
159
2

6
2
0
36
42
5
−6
1
1
56
55
3
0
7
1
223
236
2
0
15
1
38
30
2
−1
6
2
233
248
3

7
2
0
37
49
7
−5
1
1
107
120
2
1
7
1
213
220
3
1
15
1
38
30
5
0
6
2
529
545
4

1
3
0
352
375
3
−4
1
1
162
152
4
2
7
1
91
93
2
2
15
1
34
46
6
1
6
2
238
248
11

2
3
0
39
35
3
−2
1
1
338
350
3
3
7
1
136
137
1
3
15
1
27
4
5
2
6
2
152
158
2

3
3
0
58
55
2
−1
1
1
1141
1205
14
4
7
1
174
165
1
−2
16
1
24
27
7
3
6
2
131
128
1

4
3
0
84
80
1
1
1
1
1134
1206
11
5
7
1
160
158
2
−1
16
1
27
13
6
4
6
2
77
77
2

5
3
0
43
42
8
4
1
1
163
152
1
6
7
1
33
17
24
0
16
1
18
4
17
5
6
2
61
66
2

6
3
0
54
51
5
5
1
1
109
120
2
−6
8
1
61
46
10
1
16
1
33
13
8
6
6
2
69
66
3

7
3
0
34
7
7
6
1
1
56
55
11
−5
8
1
65
60
11
2
16
1
20
28
6
−6
7
2
39
49
13

0
4
0
114
118
2
7
1
1
19
16
18
−4
8
1
52
51
2
0
17
1
24
32
5
−5
7
2
96
98
3

1
4
0
17
3
3
−7
2
1
38
15
7
−3
8
1
150
145
1
1
17
1
17
3
17
−4
7
2
65
63
2

2
4
0
88
82
1
−6
2
1
41
44
4
−2
8
1
86
88
1
0
0
2
393
405
5
−3
7
2
99
90
2

4
4
0
87
87
1
−5
2
1
28
16
5
−1
8
1
68
69
5
1
0
2
332
336
8
−2
7
2
141
157
2

5
4
0
19
15
18
−4
2
1
256
252
5
0
8
1
378
391
3
2
0
2
412
409
8
−1
7
2
442
439
5

6
4
0
99
104
5
−3
2
1
108
98
2
1
8
1
69
68
2
4
0
2
137
137
3
0
7
2
252
268
2

7
4
0
66
56
4
−2
2
1
98
100
2
2
8
1
89
87
2
−6
1
2
34
44
5
1
7
2
447
439
14

1
5
0
17
4
7
−1
2
1
465
481
4
3
8
1
152
145
1
−5
1
2
114
119
4
2
7
2
146
157
2

2
5
0
72
64
1
0
2
1
15
2
3
4
8
1
54
51
6
−4
1
2
52
49
2
3
7
2
98
89
1

3
5
0
108
106
6
1
2
1
478
482
4
5
8
1
67
59
4
−2
1
2
174
178
1
4
7
2
69
63
2

4
5
0
86
82
1
2
2
1
93
99
2
6
8
1
46
46
4
−1
1
2
599
599
5
5
7
2
102
97
2

5
5
0
34
29
3
4
2
1
257
252
2
−6
9
1
37
28
12
0
1
2
166
164
2
6
7
2
51
48
4

6
5
0
29
22
6
5
2
1
17
16
8
−5
9
1
84
71
3
2
1
2
178
178
2
−6
8
2
20
16
13

7
5
0
57
41
6
6
2
1
41
44
6
−4
9
1
105
103
1
4
1
2
50
49
2
−5
8
2
53
52
4

0
6
0
645
708
8
7
2
1
17
14
16
−3
9
1
156
151
1
5
1
2
119
118
2
−4
8
2
118
118
1

1
6
0
360
437
50
−7
3
1
41
49
6
−2
9
1
54
46
1
6
1
2
47
44
3
−3
8
2
92
90
4

2
6
0
101
96
21
−6
3
1
52
50
4
−1
9
1
194
201
8
7
1
2
59
55
5
−2
8
2
40
37
2

3
6
0
36
39
3
−5
3
1
171
175
1
0
9
1
227
233
2
−7
2
2
39
34
6
−1
8
2
325
343
4

4
6
0
19
17
4
−4
3
1
239
231
3
1
9
1
190
201
7
−6
2
2
106
111
2
0
8
2
165
186
2

5
6
0
80
76
5
−3
3
1
457
454
6
2
9
1
50
46
3
−5
2
2
211
211
3
1
8
2
312
344
4

6
6
0
48
44
4
−2
3
1
306
308
4
3
9
1
157
151
1
−4
2
2
74
77
1
2
8
2
38
37
1

1
7
0
31
28
3
−1
3
1
375
403
4
4
9
1
114
103
1
−3
2
2
385
373
5
3
8
2
92
91
1

2
7
0
110
128
25
0
3
1
358
411
19
5
9
1
74
71
5
−2
2
2
96
91
1
4
8
2
118
118
3

3
7
0
72
70
1
1
3
1
394
402
3
6
9
1
36
28
6
−1
2
2
614
632
19
5
8
2
54
52
4

4
7
0
79
78
2
2
3
1
304
307
4
−5
10
1
54
57
4
0
2
2
371
373
7
6
8
2
32
16
15

5
7
0
171
167
2
3
3
1
472
455
6
−4
10
1
107
110
3
1
2
2
623
632
8
−6
9
2
76
71
5

6
7
0
49
48
4
4
3
1
240
231
2
−3
10
1
168
166
1
2
2
2
105
92
2
−5
9
2
42
36
6

0
8
0
134
137
2
5
3
1
169
176
3
−2
10
1
79
79
3
4
2
2
80
78
1
−4
9
2
170
164
2

1
8
0
226
226
8
6
3
1
44
50
5
−1
10
1
139
149
2
5
2
2
211
211
6
−3
9
2
83
82
1

2
8
0
211
196
3
7
3
1
54
49
5
0
10
1
127
138
1
6
2
2
116
111
3
−2
9
2
44
39
2

3
8
0
66
64
1
−7
4
1
46
41
5
1
10
1
145
148
1
7
2
2
34
35
7
−1
9
2
77
79
1

4
8
0
315
302
2
−6
4
1
81
84
2
2
10
1
74
79
1
−7
3
2
69
71
4
0
9
2
84
93
3

5
8
0
67
63
3
−5
4
1
34
26
20
3
10
1
168
165
1
−6
3
2
75
81
4
1
9
2
80
79
2

6
8
0
38
28
6
−4
4
1
171
165
1
4
10
1
107
110
2
−5
3
2
112
104
1
2
9
2
40
38
1

1
9
0
247
260
7
−3
4
1
189
193
3
5
10
1
62
57
4
−4
3
2
147
144
3
3
9
2
85
82
1

2
9
0
243
244
2
−2
4
1
199
199
3
−5
11
1
22
6
13
−3
3
2
190
177
3
4
9
2
172
164
4

3
9
0
193
186
2
−1
4
1
346
367
4
−4
11
1
77
79
2
−2
3
2
105
107
2
5
9
2
25
36
9

4
9
0
405
398
3
0
4
1
450
520
19
−3
11
1
51
50
1
−1
3
2
395
396
14
6
9
2
77
71
6

5
9
0
8
2
8
1
4
1
356
368
13
−2
11
1
70
71
1
0
3
2
252
272
12
−5
10
2
29
11
11

6
9
0
81
75
7
2
4
1
195
200
2
−1
11
1
92
93
2
1
3
2
391
396
5
−4
10
2
100
99
4

0
10
0
119
124
2
3
4
1
182
194
3
0
11
1
98
100
2
2
3
2
108
107
2
−3
10
2
176
168
3

1
10
0
54
49
1
4
4
1
176
166
3
1
11
1
94
93
2
4
3
2
146
144
1
−2
10
2
145
135
2

2
10
0
127
124
1
5
4
1
27
26
4
2
11
1
68
71
1
5
3
2
108
103
4
−1
10
2
167
159
3

3
10
0
116
115
1
6
4
1
83
84
3
3
11
1
52
50
2
6
3
2
89
81
3
0
10
2
187
189
3

4
10
0
26
0
5
7
4
1
37
41
6
4
11
1
79
79
2
7
3
2
75
70
3
1
10
2
168
158
2

5
10
0
63
63
4
−7
5
1
58
45
5
5
11
1
6
6
5
−6
4
2
95
101
2
2
10
2
142
135
1

1
11
0
77
75
2
−6
5
1
26
18
16
−5
12
1
49
46
8
−5
4
2
75
79
4
3
10
2
177
168
1

2
11
0
46
45
3
−5
5
1
79
76
2
−4
12
1
40
35
4
−4
4
2
172
175
3
4
10
2
99
100
3

3
11
0
15
15
5
−4
5
1
44
46
1
−3
12
1
52
55
2
−3
4
2
241
230
3
5
10
2
33
11
14

4
11
0
142
141
2
−3
5
1
136
137
2
−2
12
1
162
161
1
−2
4
2
431
439
5
−5
11
2
69
66
3

5
11
0
46
35
14
−2
5
1
337
336
4
−1
12
1
159
150
4
−1
4
2
58
62
2
−4
11
2
49
45
3

0
12
0
58
55
3
−1
5
1
171
174
2
0
12
1
113
117
2
0
4
2
242
268
20
−3
11
2
87
87
2

1
12
0
67
69
1
0
5
1
274
294
2
1
12
1
163
151
3
1
4
2
69
63
1
−2
11
2
106
103
4

2
12
0
145
145
1
1
5
1
174
174
2
2
12
1
158
161
1
2
4
2
438
438
7
−1
11
2
108
119
2

3
12
0
43
40
4
2
5
1
343
336
4
3
12
1
56
55
2
3
4
2
247
229
3
0
11
2
96
88
2

4
12
0
32
24
4
3
5
1
126
137
1
4
12
1
32
35
10
4
4
2
177
175
2
1
11
2
112
118
1

5
12
0
45
36
4
4
5
1
45
46
2
5
12
1
48
46
13
5
4
2
80
79
2
2
11
2
105
104
1

1
13
0
26
9
7
5
5
1
82
76
3
−4
13
1
41
23
9
6
4
2
106
101
3
3
11
2
87
87
2

2
13
0
161
164
1
6
5
1
24
18
14
−3
13
1
67
71
2
7
4
2
50
40
5
4
11
2
41
45
4

3
13
0
137
141
1
7
5
1
68
45
4
−2
13
1
45
47
2
−6
5
2
85
79
4
5
11
2
70
66
3

4
13
0
43
42
9
−6
6
1
87
91
4
−1
13
1
49
38
2
−5
5
2
94
96
7
−5
12
2
59
63
20

0
14
0
79
84
2
−5
6
1
125
128
2
0
13
1
23
25
3
−4
5
2
188
188
1
−4
12
2
65
59
3

1
14
0
40
32
2
−4
6
1
61
61
1
1
13
1
54
38
5
−3
5
2
162
167
3
−3
12
2
46
48
2

2
14
0
32
26
4
−3
6
1
77
73
1
2
23
1
50
47
4
−2
5
2
181
176
3
−2
12
2
39
46
6

3
14
0
87
89
2
−2
6
1
73
71
2
3
13
1
70
71
2
−1
5
2
151
146
2
−1
12
2
43
27
9

4
14
0
49
43
4
−1
6
1
327
325
4
4
13
1
41
23
7
0
5
2
901
990
15
0
12
2
21
13
3

1
12
2
38
27
9
1
4
3
305
297
3
0
11
3
72
67
1
1
3
4
316
326
2
−2
10
4
70
68
2

2
12
2
41
46
2
2
4
3
115
120
2
1
11
3
65
63
2
4
3
4
11
8
10
−1
10
4
81
80
1

3
12
2
43
48
2
4
4
3
86
85
2
2
11
3
141
137
2
5
3
4
38
44
3
0
10
4
49
49
1

4
12
2
66
59
3
5
4
3
139
136
3
3
11
3
159
153
1
6
3
4
81
78
3
1
10
4
81
79
3

5
12
2
53
63
9
6
4
3
72
68
4
4
11
3
130
130
2
7
3
4
42
41
5
2
10
4
70
67
2

4
13
2
34
34
8
7
4
3
48
42
5
5
11
3
96
92
2
−6
4
4
84
94
3
3
10
4
105
104
2

3
13
2
87
90
2
−6
5
3
52
51
11
−5
12
3
38
48
8
−5
4
4
28
32
4
4
10
4
77
68
2

2
13
2
36
20
5
−5
5
3
172
171
2
−4
12
3
29
25
5
−4
4
4
142
142
1
5
10
4
68
60
3

1
13
2
116
120
2
−4
5
3
76
72
2
−3
12
3
135
135
4
−3
4
4
235
222
3
−5
11
4
119
116
2

0
13
2
66
62
1
−3
5
3
21
12
7
−2
12
3
80
84
2
−2
4
4
186
180
2
−4
11
4
24
11
7

1
13
2
117
120
3
−2
5
3
223
216
3
−1
12
3
181
175
3
−1
4
4
400
390
8
−3
11
4
113
111
2

2
13
2
30
20
7
−1
5
3
186
196
2
0
12
3
45
49
2
0
4
4
327
325
3
−2
11
4
86
83
2

3
13
2
89
90
2
0
5
3
733
738
46
1
12
3
176
174
3
1
4
4
392
390
9
−1
11
4
164
160
2

4
13
2
38
34
5
1
5
3
197
196
2
2
12
3
81
84
3
2
4
4
186
180
6
0
11
4
109
111
1

4
14
2
60
57
8
2
5
3
225
217
3
3
12
3
133
136
1
3
4
4
208
222
3
1
11
4
162
161
2

3
14
2
41
43
3
3
5
3
15
12
10
4
12
3
15
24
14
4
4
4
153
142
2
2
11
4
83
83
1

2
14
2
56
61
2
4
5
3
79
73
2
5
12
3
50
48
3
5
4
4
31
32
4
3
11
4
117
111
1

1
14
2
34
25
3
5
5
3
176
171
4
−4
13
3
25
20
13
6
4
4
90
94
3
4
11
4
32
12
6

0
14
2
92
92
1
6
5
3
54
51
5
−3
13
3
64
62
2
7
4
4
25
6
10
5
11
4
112
115
2

1
14
2
22
25
6
−6
6
3
52
51
7
−2
13
3
38
36
2
−6
5
4
84
99
4
−5
12
4
59
47
8

2
14
2
61
61
4
−5
6
3
93
93
3
−1
13
3
49
48
2
−5
5
4
133
138
5
−4
12
4
19
4
10

3
14
2
41
42
4
−4
6
3
120
114
2
0
13
3
34
24
5
−4
5
4
57
59
2
−3
12
4
116
121
2

4
14
2
53
57
5
−3
6
3
62
60
2
1
13
3
44
48
3
−3
5
4
147
150
2
−2
12
4
44
32
5

3
15
2
36
36
4
−2
6
3
238
243
3
2
13
3
48
36
12
−2
5
4
177
182
3
−1
12
4
125
117
3

2
15
2
47
44
4
−1
6
3
88
86
2
3
13
3
63
62
3
−1
5
4
258
237
2
0
12
4
64
62
2

1
15
2
21
10
7
0
6
3
136
146
1
4
13
3
38
20
8
0
5
4
339
335
20
1
12
4
119
117
1

0
15
2
33
36
3
1
6
3
92
84
1
−4
14
3
37
38
8
1
5
4
247
237
2
2
12
4
41
32
3

1
15
2
25
10
5
2
6
3
233
242
3
−3
14
3
96
96
2
2
5
4
166
181
1
3
12
4
120
121
2

2
15
2
40
44
4
3
6
3
61
61
2
−2
14
3
94
106
2
3
5
4
152
151
2
4
12
4
31
4
31

3
15
2
34
37
4
4
6
3
125
114
2
−1
14
3
31
18
4
4
5
4
60
59
2
5
12
4
46
47
5

2
16
2
24
16
5
5
6
3
97
93
2
0
14
3
27
29
4
5
5
4
132
138
2
−4
13
4
59
56
3

1
16
2
27
29
6
6
6
3
58
51
4
1
14
3
24
19
5
6
5
4
94
99
3
−3
13
4
77
80
1

0
16
2
37
17
4
−6
7
3
32
23
9
2
14
3
101
106
3
−6
6
4
66
73
11
−2
13
4
98
98
1

1
16
2
29
29
3
−5
7
3
53
57
2
3
14
3
99
96
5
−5
6
4
59
58
3
−1
13
4
37
42
6

2
16
2
23
16
6
−4
7
3
232
230
2
4
14
3
37
38
4
−4
6
4
77
79
2
0
13
4
58
64
3

0
17
2
19
14
8
−3
7
3
59
56
2
−3
15
3
35
35
9
−3
6
4
67
64
1
1
13
4
40
42
3

1
17
2
37
28
6
−2
7
3
171
181
3
−2
15
3
36
33
3
−2
6
4
173
169
3
2
13
4
98
99
2

1
0
3
986
1006
11
−1
7
3
228
222
3
−1
15
3
32
21
6
−1
6
4
330
348
4
3
13
4
76
80
2

2
0
3
115
121
2
0
7
3
379
403
3
0
15
3
39
34
3
0
6
4
55
58
4
4
13
4
50
57
7

4
0
3
324
311
5
1
7
3
230
222
6
1
15
3
36
21
7
1
6
4
350
349
7
−4
14
4
62
58
6

6
0
3
57
51
14
2
7
3
167
180
3
2
15
3
31
33
6
2
6
4
157
169
2
−3
14
4
67
64
2

6
1
3
73
67
3
3
7
3
57
56
1
3
15
3
40
35
4
3
6
4
68
64
1
−2
14
4
22
14
5

5
1
3
253
250
9
4
7
3
231
230
7
−2
16
3
34
35
2
4
6
4
82
79
6
−1
14
4
38
39
6

4
1
3
176
170
3
5
7
3
59
57
3
−1
16
3
28
7
5
5
6
4
58
58
2
0
14
4
77
83
2

3
1
3
392
392
7
6
7
3
38
23
16
0
16
3
52
55
2
6
6
4
77
73
4
1
14
4
38
39
4

2
1
3
207
207
2
−6
8
3
32
28
10
1
16
3
29
7
6
−6
7
4
55
36
6
2
14
4
20
15
9

1
1
3
101
95
2
−5
8
3
31
15
4
2
16
3
42
36
4
−5
7
4
101
105
3
3
14
4
64
64
3

0
1
3
1115
1114
19
−4
8
3
73
78
2
0
17
3
68
76
3
−4
7
4
57
57
2
4
14
4
56
59
4

1
1
3
97
96
2
−3
8
3
193
191
2
0
0
4
372
431
7
−3
7
4
35
36
1
−3
15
4
42
42
2

2
1
3
205
206
2
−2
8
3
189
190
4
1
0
4
549
576
4
−2
7
4
147
139
3
−2
15
4
56
66
5

4
1
3
176
169
2
−1
8
3
310
324
4
2
0
4
64
65
1
−1
7
4
302
287
4
−1
15
4
49
55
8

5
1
3
252
249
9
0
8
3
234
243
11
4
0
4
38
42
23
0
7
4
175
175
14
0
15
4
44
36
3

6
1
3
69
66
2
1
8
3
308
325
7
5
0
4
99
100
3
1
7
4
299
287
4
1
15
4
61
55
3

7
1
3
42
18
6
2
8
3
185
191
3
6
0
4
116
121
7
2
7
4
142
139
2
2
15
4
54
66
4

6
2
3
77
80
2
3
8
3
188
191
2
−6
1
4
66
64
5
3
7
4
39
36
2
3
15
4
46
42
7

5
2
3
59
70
2
4
8
3
79
78
2
−5
1
4
100
102
2
4
7
4
58
57
2
−2
16
4
36
41
8

4
2
3
87
91
3
5
8
3
27
15
22
−4
1
4
90
77
2
5
7
4
108
106
2
−1
16
4
55
66
2

3
2
3
223
231
3
6
8
3
25
28
8
−3
1
4
141
148
1
6
7
4
49
36
5
0
16
4
24
6
6

2
2
3
377
364
3
−6
9
3
59
52
6
−2
1
4
112
111
2
−6
8
4
45
36
7
1
16
4
61
65
4

1
2
3
715
744
16
−5
9
3
82
80
4
−1
1
4
489
481
4
−5
8
4
176
177
2
2
16
4
32
41
7

0
2
3
1539
1543
19
−4
9
3
261
247
2
0
1
4
731
731
10
−4
8
4
88
93
1
1
0
5
97
112
2

1
2
3
723
744
8
−3
9
3
116
117
3
1
1
4
473
481
6
−3
8
4
207
208
6
2
0
5
313
371
45

2
2
3
359
364
4
−2
9
3
72
67
2
2
1
4
108
111
2
−2
8
4
119
121
3
3
0
5
180
174
2

4
2
3
83
91
1
−1
9
3
40
31
3
4
1
4
90
77
4
−1
8
4
231
230
6
4
0
5
115
109
2

5
2
3
63
70
1
0
9
3
52
55
2
5
1
4
102
103
5
0
8
4
180
186
10
5
0
5
316
289
4

6
2
3
86
80
3
1
9
3
32
31
1
6
1
4
74
64
4
1
8
4
236
230
7
−6
1
5
62
62
4

7
2
3
25
20
11
2
9
3
69
67
1
7
1
4
38
45
7
2
8
4
124
122
2
−5
1
5
209
197
3

6
3
3
79
84
4
3
9
3
116
117
1
−6
2
4
30
20
9
3
8
4
211
208
4
−4
1
5
136
128
2

5
3
3
127
121
2
4
9
3
256
247
4
−5
2
4
203
190
3
4
8
4
91
93
2
−3
1
5
101
112
2

4
3
3
217
214
8
5
9
3
83
80
5
−4
2
4
136
129
2
5
8
4
181
177
2
−2
1
5
261
256
2

3
3
3
87
77
2
6
9
3
66
52
9
−3
2
4
329
324
3
6
8
4
46
36
5
−1
1
5
290
294
6

2
3
3
217
219
2
−5
10
3
65
65
4
−2
2
4
236
241
2
−6
9
4
48
41
7
0
1
5
244
248
2

1
3
3
676
688
22
−4
10
3
146
144
1
−1
2
4
471
497
15
−5
9
4
51
48
3
1
1
5
287
295
3

0
3
3
461
472
10
−3
10
3
37
35
2
0
2
4
952
922
20
−4
9
4
107
104
3
2
1
5
249
257
3

1
3
3
675
687
5
−2
10
3
85
74
3
1
2
4
483
497
8
−3
9
4
74
74
1
4
1
5
135
128
2

2
3
3
228
219
3
−1
10
3
251
228
2
2
2
4
232
242
3
−2
9
4
101
98
2
5
1
5
201
197
3

4
3
3
220
213
2
0
10
3
43
41
1
4
2
4
125
129
1
−1
9
4
72
69
1
6
1
5
76
61
4

5
3
3
130
120
7
1
10
3
237
228
8
5
2
4
203
191
3
0
9
4
176
174
4
7
1
5
25
46
14

6
3
3
81
84
3
2
10
3
83
74
1
6
2
4
27
20
11
1
9
4
68
69
1
−5
2
5
118
119
2

7
3
3
54
45
5
3
10
3
34
35
2
7
2
4
38
9
7
2
9
4
102
97
4
−4
2
5
32
44
4

6
4
3
69
68
3
4
10
3
147
144
3
−6
3
4
82
78
3
3
9
4
76
73
2
−3
2
5
224
218
2

5
4
3
135
136
2
5
10
3
74
65
3
−5
3
4
44
44
7
4
9
4
104
104
2
−2
2
5
262
273
4

4
4
3
79
85
1
−5
11
3
96
92
4
−4
3
4
15
9
9
5
9
4
53
48
5
−1
2
5
713
749
40

3
4
3
109
103
2
−4
11
3
130
130
3
−3
3
4
275
287
4
6
9
4
36
41
6
0
2
5
403
403
3

2
4
3
119
121
2
−3
11
3
157
153
4
−2
3
4
262
259
7
−5
10
4
59
60
8
1
2
5
716
750
7

1
4
3
300
297
9
−2
11
3
148
137
2
−1
3
4
315
325
15
−4
10
4
74
68
3
2
2
5
262
272
3

0
4
3
261
268
3
−1
11
3
58
63
1
0
3
4
241
241
4
−3
10
4
104
104
2
4
2
5
41
44
3

5
2
5
124
119
2
−3
10
5
73
75
1
7
2
6
35
28
8
4
10
6
59
52
4
−3
4
7
172
165
1

6
2
5
66
56
4
−2
10
5
32
29
2
−4
3
6
147
143
2
5
10
6
92
97
2
−2
4
7
151
142
2

7
2
5
38
37
6
−1
10
5
109
112
2
−3
3
6
127
134
2
−5
11
6
34
22
7
−1
4
7
314
293
3

5
3
5
78
76
3
0
10
5
20
21
5
−2
3
6
361
357
3
−4
11
6
129
126
2
0
4
7
148
130
1

4
3
5
105
98
2
1
10
5
111
112
2
−1
3
6
287
275
2
−3
11
6
30
29
6
1
4
7
302
292
4

3
3
5
226
216
2
2
10
5
39
29
8
0
3
6
283
282
12
−2
11
6
113
115
1
3
4
7
174
165
2

2
3
5
206
194
4
3
10
5
70
75
1
1
3
6
273
276
2
−1
11
6
170
176
5
4
4
7
75
79
3

1
3
5
158
156
2
4
10
5
43
41
4
2
3
6
356
357
4
0
11
6
23
20
2
5
4
7
80
78
3

0
3
5
353
335
5
5
10
5
108
110
4
4
3
6
145
143
3
1
11
6
170
176
2
6
4
7
82
81
4

1
3
5
159
156
3
−5
11
5
33
27
6
5
3
6
201
198
3
2
11
6
111
116
2
−4
5
7
61
60
3

4
3
5
99
97
3
−4
11
5
90
84
2
6
3
6
61
50
5
3
11
6
31
29
16
−3
5
7
107
104
1

5
3
5
80
76
3
−3
11
5
29
27
3
−3
4
6
86
87
2
4
11
6
124
125
3
−2
5
7
162
153
4

6
3
5
60
51
5
−2
11
5
104
99
1
−2
4
6
113
101
1
5
11
6
23
22
7
−1
5
7
152
140
2

7
3
5
32
6
8
−1
11
5
97
106
2
−1
4
6
539
523
13
−4
12
6
38
33
6
0
5
7
181
186
28

4
4
5
20
21
19
0
11
5
18
2
8
0
4
6
65
59
1
−3
12
6
129
128
4
1
5
7
145
139
1

3
4
5
203
196
3
1
11
5
102
106
2
1
4
6
530
523
6
−2
12
6
100
93
3
2
5
7
152
153
2

2
4
5
248
242
5
2
11
5
100
100
1
2
4
6
102
101
2
−1
12
6
91
89
3
3
5
7
106
104
2

1
4
5
73
71
2
3
11
5
39
27
6
3
4
6
87
87
2
0
12
6
111
112
1
4
5
7
63
60
1

0
4
5
158
171
5
4
11
5
83
84
3
4
4
6
103
99
3
1
12
6
90
89
1
5
5
7
174
176
3

1
4
5
72
71
1
5
11
5
35
27
7
5
4
6
52
54
4
2
12
6
94
94
2
6
5
7
54
66
5

3
4
5
180
196
3
−4
12
5
52
55
4
6
4
6
72
60
4
3
12
6
131
128
3
−4
6
7
105
107
2

4
4
5
8
20
7
−3
12
5
53
44
4
−4
5
6
62
62
2
4
12
6
30
32
7
−3
6
7
135
133
1

5
4
5
58
63
2
−2
12
5
86
81
1
−3
5
6
27
8
3
−4
13
6
28
16
12
−2
6
7
171
160
1

6
4
5
126
122
3
−1
12
5
39
41
2
−2
5
6
166
164
2
−3
13
6
114
124
5
−1
6
7
201
200
2

5
5
5
46
42
5
0
12
5
31
5
7
−1
5
6
301
282
3
−2
13
6
104
105
2
0
6
7
198
195
3

4
5
5
26
23
3
1
12
5
43
41
2
0
5
6
109
98
1
−1
13
6
117
121
4
1
6
7
194
200
3

3
5
5
50
47
1
2
12
5
82
81
1
1
5
6
291
282
4
0
13
6
26
25
4
2
6
7
177
160
2

2
5
5
428
416
4
3
12
5
50
44
3
3
5
6
10
8
9
1
13
6
117
121
2
3
6
7
134
134
1

1
5
5
126
136
2
4
12
5
58
54
3
4
5
6
68
62
1
2
13
6
103
105
1
4
6
7
103
107
2

0
5
5
275
251
4
5
12
5
41
29
5
5
5
6
34
32
8
3
13
6
123
124
3
5
6
7
112
112
3

1
5
5
120
136
4
−4
13
5
31
22
10
6
5
6
83
73
4
4
13
6
27
16
8
6
6
7
46
35
6

3
5
5
50
47
1
−3
13
5
51
47
5
−5
6
6
68
64
5
−3
14
6
21
28
6
−5
7
7
108
106
6

4
5
5
26
23
4
−2
13
5
72
71
4
−4
6
6
52
48
2
−2
14
6
56
46
5
−4
7
7
88
81
1

5
5
5
46
42
4
−1
13
5
50
51
6
−3
6
6
112
107
1
−1
14
6
10
18
10
−3
7
7
63
66
4

6
5
5
100
92
3
0
13
5
33
33
5
−2
6
6
68
63
2
0
14
6
53
49
2
−2
7
7
82
81
1

5
6
5
65
62
5
1
13
5
53
51
2
−1
6
6
172
175
4
1
14
6
26
18
12
−1
7
7
75
76
1

4
6
5
56
57
2
2
13
5
71
72
3
0
6
6
240
239
25
2
14
6
47
47
7
0
7
7
258
286
23

3
6
5
95
97
1
3
13
5
50
47
3
1
6
6
168
175
2
3
14
6
31
28
5
1
7
7
74
76
2

2
6
5
173
162
4
4
13
5
33
22
5
2
6
6
60
63
2
−2
15
6
37
40
6
2
7
7
85
81
2

1
6
5
224
223
3
−3
14
5
38
39
4
3
6
6
113
107
1
−1
15
6
42
42
12
3
7
7
58
66
2

0
6
5
15
6
14
−2
14
5
88
91
2
4
6
6
49
48
2
0
15
6
61
68
6
4
7
7
84
81
2

1
6
5
223
222
3
−1
14
5
43
41
5
5
6
6
67
63
4
1
15
6
42
43
4
5
7
7
98
107
3

2
6
5
165
163
2
0
14
5
59
61
2
6
6
6
62
68
4
2
15
6
42
40
7
6
7
7
49
42
5

3
6
5
100
98
2
1
14
5
41
41
2
−5
7
6
124
120
5
3
15
6
56
57
5
−5
8
7
32
27
6

4
6
5
64
56
1
2
14
5
92
91
4
−4
7
6
57
58
1
−1
16
6
51
52
6
−4
8
7
90
93
3

5
6
5
61
62
4
3
14
5
35
39
9
−3
7
6
188
193
3
0
16
6
12
1
12
−3
8
7
104
103
1

6
6
5
76
68
4
−3
15
5
36
31
10
−2
7
6
53
55
1
1
16
6
52
52
3
−2
8
7
72
74
1

6
7
5
24
64
23
−2
15
5
74
80
2
−1
7
6
134
123
2
1
0
7
35
42
6
−1
8
7
268
261
1

5
7
5
83
89
4
−1
15
5
21
10
14
0
7
6
171
186
14
2
0
7
224
211
3
0
8
7
98
105
1

4
7
5
47
47
2
0
15
5
45
51
3
1
7
6
130
123
2
3
0
7
28
30
4
1
8
7
272
261
2

3
7
5
82
82
1
1
15
5
22
10
22
2
7
6
53
55
5
4
0
7
108
111
2
2
8
7
76
74
3

2
7
5
173
177
1
2
15
5
75
80
3
3
7
6
189
193
3
5
0
7
73
75
3
3
8
7
102
103
2

1
7
5
201
203
7
3
15
5
40
31
4
4
7
6
53
57
2
6
0
7
17
1
16
4
8
7
91
93
1

0
7
5
343
344
27
−2
16
5
26
10
9
5
7
6
118
120
2
−6
1
7
51
64
5
5
8
7
27
27
9

1
7
5
196
204
6
−1
16
5
64
63
3
6
7
6
43
35
6
−5
1
7
135
132
2
6
8
7
53
51
4

2
7
5
171
177
1
0
16
5
35
35
2
−5
8
6
67
61
9
−4
1
7
180
176
2
−5
9
7
22
6
21

3
7
5
81
83
1
1
16
5
59
63
2
−4
8
6
67
67
2
−3
1
7
162
168
2
−4
9
7
63
62
2

4
7
5
46
46
2
2
16
5
25
10
11
−3
8
6
39
35
1
−2
1
7
132
132
2
−3
9
7
95
90
1

5
7
5
82
89
2
0
0
6
402
451
15
−2
8
6
68
65
2
−1
1
7
191
189
4
−2
9
7
121
119
1

6
7
5
63
64
4
1
0
6
69
75
3
−1
8
6
112
115
1
0
1
7
250
250
2
−1
9
7
197
194
2

6
8
5
43
20
7
2
0
6
27
29
4
0
8
6
18
13
12
1
1
7
180
189
2
0
9
7
178
178
1

5
8
5
69
59
7
3
0
6
85
80
2
1
8
6
112
114
5
2
1
7
128
132
2
1
9
7
188
194
6

4
8
5
117
117
1
5
0
6
180
166
3
2
8
6
68
65
1
3
1
7
163
168
2
2
9
7
117
118
2

3
8
5
133
128
2
6
0
6
112
109
3
3
8
6
37
35
3
4
1
7
190
176
3
3
9
7
97
90
3

2
8
5
65
62
2
−6
1
6
205
205
3
4
8
6
69
67
1
5
1
7
138
132
3
4
9
7
68
62
3

1
8
5
371
376
3
−5
1
6
89
87
2
5
8
6
60
61
3
6
1
7
63
63
4
−5
10
7
43
43
7

0
8
5
24
31
6
−4
1
6
132
125
2
6
8
6
36
16
6
−5
2
7
93
90
3
−4
10
7
95
98
2

1
8
5
380
376
8
−3
1
6
215
217
3
−5
9
6
122
121
2
−4
2
7
31
31
4
−3
10
7
160
151
1

2
8
5
61
62
2
−2
1
6
329
336
6
−4
9
6
158
153
2
−3
2
7
61
70
2
−2
10
7
134
135
1

3
8
5
130
128
2
−1
1
6
174
173
1
−3
9
6
97
94
2
−2
2
7
140
132
4
−1
10
7
127
125
3

4
8
5
120
117
4
0
1
6
155
165
1
−2
9
6
133
129
3
−1
2
7
394
385
3
0
10
7
159
158
1

5
8
5
67
58
3
1
1
6
160
173
1
−1
9
6
105
101
1
0
2
7
111
114
1
1
10
7
125
125
1

6
8
5
33
20
7
2
1
6
333
336
4
0
9
6
143
153
2
1
2
7
378
385
6
2
10
7
135
135
1

5
9
5
28
33
8
3
1
6
207
218
3
1
9
6
101
101
1
4
2
7
37
30
3
3
10
7
154
151
3

4
9
5
96
98
1
4
1
6
127
124
2
2
9
6
134
129
4
5
2
7
87
91
3
4
10
7
93
98
5

3
9
5
94
92
1
5
1
6
91
87
3
3
9
6
96
94
2
6
2
7
67
76
4
5
10
7
31
43
6

2
9
5
138
136
2
6
1
6
207
205
3
4
9
6
153
153
3
−4
3
7
203
197
3
−5
11
7
54
42
4

1
9
5
165
157
2
−5
2
6
199
193
3
5
9
6
120
121
8
−3
3
7
104
105
2
−4
11
7
57
60
4

0
9
5
144
144
2
−4
2
6
77
79
2
−5
10
6
94
97
3
−2
3
7
355
347
9
−3
11
7
57
49
3

1
9
5
158
157
4
−3
2
6
121
120
1
−4
10
6
57
52
3
−1
3
7
387
366
3
−2
11
7
53
54
2

2
9
5
143
135
4
−2
2
6
295
299
7
−3
10
6
149
150
2
0
3
7
176
151
2
−1
11
7
53
46
4

3
9
5
91
91
2
−1
2
6
453
433
4
−2
10
6
197
196
2
1
3
7
375
367
5
0
11
7
42
39
2

4
9
5
99
98
4
0
2
6
271
248
2
−1
10
6
186
182
4
2
3
7
347
346
4
1
11
7
51
46
1

5
9
5
37
33
5
1
2
6
432
433
5
0
10
6
90
98
1
3
3
7
98
105
2
2
11
7
61
55
4

6
9
5
38
33
6
4
2
6
81
78
2
1
10
6
182
182
2
4
3
7
209
197
3
3
11
7
53
48
3

5
10
5
115
110
2
5
2
6
203
193
3
2
10
6
196
196
3
5
3
7
102
101
2
4
11
7
62
61
3

4
10
5
50
40
4
6
2
6
83
80
4
3
10
6
145
150
2
6
3
7
46
48
6
5
11
7
44
42
5

4
12
7
29
16
11
2
5
8
163
159
2
−1
14
8
38
38
5
4
7
9
89
87
2
2
2
10
177
185
3

3
12
7
79
84
3
3
5
8
25
21
3
0
14
8
23
15
9
5
7
9
39
27
25
3
2
10
85
87
3

2
12
7
126
117
2
4
5
8
33
38
2
1
14
8
43
37
3
−5
8
9
31
43
11
4
2
10
174
187
3

1
12
7
25
20
4
5
5
8
68
64
3
2
14
8
27
25
6
−4
8
9
58
57
4
−4
3
10
182
198
3

0
12
7
308
305
6
6
5
8
104
100
3
3
14
8
20
24
19
−3
8
9
52
47
2
−3
3
10
173
176
4

1
12
7
30
20
3
−4
6
8
57
59
2
−2
15
8
44
38
3
−2
8
9
150
146
2
−2
3
10
121
111
1

2
12
7
111
117
2
−3
6
8
64
61
2
−1
15
8
25
13
7
−1
8
9
74
76
2
−1
3
10
164
167
2

3
12
7
75
84
4
−2
6
8
152
140
2
0
15
8
68
63
2
0
8
9
94
99
1
0
3
10
121
121
1

4
12
7
18
16
17
−1
6
8
125
116
3
1
15
8
25
12
9
1
8
9
72
75
1
1
3
10
160
167
2

4
13
7
47
34
7
0
6
8
71
70
3
2
15
8
54
38
5
2
8
9
153
146
2
2
3
10
117
111
1

2
13
7
76
72
3
1
6
8
119
116
2
1
0
9
19
25
3
3
8
9
51
47
4
3
3
10
169
176
2

1
13
7
111
113
5
2
6
8
152
140
2
2
0
9
142
149
2
4
8
9
59
57
2
4
3
10
175
198
3

0
13
7
58
58
3
3
6
8
60
60
1
3
0
9
58
62
2
5
8
9
44
43
4
−4
4
10
71
64
3

1
13
7
109
113
1
4
6
8
58
59
1
4
0
9
160
183
2
−5
9
9
53
47
6
−3
4
10
56
55
1

2
13
7
75
72
2
5
6
8
49
41
5
5
0
9
103
105
2
−4
9
9
144
146
2
−2
4
10
43
40
2

3
13
7
26
22
7
6
6
8
49
44
5
−5
1
9
121
119
3
−3
9
9
57
60
2
−1
4
10
99
88
1

4
13
7
34
34
6
−4
7
8
80
83
1
−4
1
9
56
51
3
−2
9
9
29
21
7
0
4
10
328
328
8

3
14
7
29
28
20
−3
7
8
69
65
1
−3
1
9
26
30
5
−1
9
9
38
29
6
1
4
10
91
88
1

2
14
7
36
30
10
−2
7
8
60
58
2
−2
1
9
84
81
2
0
9
9
96
101
2
2
4
10
39
40
1

1
14
7
104
112
9
−1
7
8
94
91
1
−1
1
9
150
152
7
1
9
9
43
29
8
3
4
10
61
55
3

0
14
7
36
35
3
0
7
8
88
90
3
0
1
9
179
181
6
2
9
9
36
20
4
4
4
10
63
64
3

1
14
7
108
112
2
1
7
8
93
92
2
1
1
9
147
152
1
3
9
9
62
60
3
5
4
10
61
77
3

2
14
7
28
30
6
2
7
8
62
59
7
2
1
9
80
81
2
4
9
9
149
146
3
−4
5
10
166
170
3

3
14
7
37
28
9
3
7
8
71
66
2
3
1
9
34
30
3
5
9
9
48
47
6
−3
5
10
73
73
2

2
15
7
56
59
3
4
7
8
78
82
1
4
1
9
47
51
3
−5
10
9
35
26
8
−2
5
10
121
118
2

1
15
7
63
69
9
5
7
8
54
55
6
5
1
9
128
119
3
−4
10
9
49
37
11
−1
5
10
150
146
1

0
15
7
94
88
2
6
7
8
67
54
4
6
1
9
51
41
5
−3
10
9
39
29
3
0
5
10
75
75
1

1
15
7
69
68
2
−5
8
8
126
123
3
−4
2
9
115
122
3
−2
10
9
112
110
1
1
5
10
147
146
2

2
15
7
56
59
3
−4
8
8
40
33
5
−3
2
9
31
30
2
−1
10
9
246
241
2
2
5
10
115
118
4

1
16
7
48
45
3
−3
8
8
147
141
1
−2
2
9
200
201
2
0
10
9
151
138
2
3
5
10
71
74
3

0
16
7
34
31
4
−2
8
8
120
116
3
−1
2
9
284
274
3
1
10
9
248
241
2
4
5
10
147
170
3

0
0
8
458
523
44
−1
8
8
36
33
3
0
2
9
541
526
4
2
10
9
105
110
2
5
5
10
26
44
10

1
0
8
55
59
1
0
8
8
162
164
1
1
2
9
273
275
2
3
10
9
31
29
4
−4
6
10
69
66
4

2
0
8
226
227
3
1
8
8
30
32
4
2
2
9
192
201
3
4
10
9
39
37
4
−3
6
10
100
100
2

3
0
8
116
115
1
2
8
8
124
116
5
3
2
9
21
30
5
−4
11
9
35
44
6
−2
6
10
41
38
2

4
0
8
115
117
12
3
8
8
144
141
1
4
2
9
107
121
4
−3
11
9
106
104
2
−1
6
10
89
82
1

5
0
8
41
51
5
4
8
8
22
33
5
5
2
9
85
78
3
−2
11
9
176
175
2
0
6
10
198
187
2

6
0
8
85
79
4
5
8
8
116
123
11
6
2
9
100
95
3
−1
11
9
35
36
3
1
6
10
87
82
1

5
1
8
178
174
3
−5
9
8
42
6
21
−3
3
9
103
105
3
0
11
9
29
18
3
2
6
10
37
38
2

4
1
8
91
83
2
−4
9
8
97
96
3
−2
3
9
21
9
4
1
11
9
41
36
4
3
6
10
103
99
2

3
1
8
65
68
2
−3
9
8
53
58
2
−1
3
9
233
217
2
2
11
9
170
175
10
4
6
10
66
67
3

2
1
8
233
239
7
−2
9
8
132
126
3
0
3
9
44
36
2
3
11
9
103
103
2
5
6
10
62
67
4

1
1
8
407
410
9
−1
9
8
159
155
3
1
3
9
220
217
3
4
11
9
48
44
3
−4
7
10
73
71
4

0
1
8
116
124
1
0
9
8
174
173
1
3
3
9
101
104
2
−4
12
9
65
61
3
−3
7
10
69
68
1

1
1
8
394
410
3
1
9
8
157
155
4
4
3
9
123
123
9
−3
12
9
84
83
5
−2
7
10
99
98
1

2
1
8
221
238
3
2
9
8
131
126
5
5
3
9
78
75
3
−2
12
9
63
60
3
−1
7
10
46
40
2

3
1
8
70
69
1
3
9
8
53
58
3
6
3
9
105
107
3
−1
12
9
140
134
1
0
7
10
48
47
2

4
1
8
85
82
6
4
9
8
94
96
2
−4
4
9
62
70
3
0
12
9
43
26
4
1
7
10
41
40
2

5
1
8
181
173
3
5
9
8
24
6
7
−3
4
9
110
111
1
1
12
9
140
134
1
2
7
10
103
98
4

6
1
8
82
74
4
−5
10
8
35
37
6
−2
4
9
269
269
1
2
12
9
57
61
6
3
7
10
62
68
3

5
2
8
35
37
5
−4
10
8
71
66
3
−1
4
9
132
129
2
3
12
9
85
83
4
4
7
10
66
71
3

4
2
8
42
40
4
−3
10
8
33
20
7
0
4
9
253
231
9
4
12
9
45
61
5
5
7
10
36
46
7

3
2
8
214
231
7
−2
10
8
112
112
2
1
4
9
126
128
1
−3
13
9
78
85
2
−4
8
10
64
64
3

2
2
8
120
121
2
−1
10
8
136
136
4
2
4
9
252
269
2
−2
13
9
67
63
2
−3
8
10
50
45
4

1
2
8
130
126
1
0
10
8
126
122
2
3
4
9
114
111
2
−1
13
9
71
72
4
−2
8
10
103
105
1

0
2
8
172
160
2
1
10
8
133
136
2
4
4
9
57
70
2
0
13
9
78
76
2
−1
8
10
43
44
2

1
2
8
124
126
1
2
10
8
115
113
5
5
4
9
84
82
3
1
13
9
70
72
2
0
8
10
92
89
1

2
2
8
109
121
1
3
10
8
27
21
5
6
4
9
28
20
9
2
13
9
66
63
14
1
8
10
46
44
3

3
2
8
219
231
2
4
10
8
66
66
5
−4
5
9
82
82
2
3
13
9
84
85
3
2
8
10
101
105
3

4
2
8
38
40
2
5
10
8
35
38
5
−3
5
9
88
88
1
−2
14
9
29
16
10
3
8
10
46
45
4

5
2
8
46
37
4
−4
11
8
21
10
20
−2
5
9
85
82
2
−1
14
9
34
23
6
4
8
10
57
64
4

6
2
8
80
82
3
−3
11
8
123
123
3
−1
5
9
90
90
2
0
14
9
16
18
16
5
8
10
54
62
5

3
3
8
161
164
2
−2
11
8
105
105
1
0
5
9
66
72
2
1
14
9
15
23
15
−4
9
10
71
73
3

2
3
8
80
80
3
−1
11
8
130
129
3
1
5
9
95
90
2
2
14
9
39
16
6
−3
9
10
77
75
1

1
3
8
492
476
4
0
11
8
34
1
5
2
5
9
84
82
4
−2
15
9
54
51
4
−2
9
10
30
30
6

0
3
8
44
42
2
1
11
8
128
129
1
3
5
9
88
88
2
−1
15
9
31
28
6
−1
9
10
64
62
2

1
3
8
486
476
10
2
11
8
100
105
2
4
5
9
81
83
2
0
15
9
75
82
2
0
9
10
45
45
1

2
3
8
78
81
2
3
11
8
121
123
2
5
5
9
40
49
5
0
0
10
131
138
2
1
9
10
64
62
3

3
3
8
160
165
7
4
11
8
27
10
8
−4
6
9
109
107
2
1
0
10
112
115
2
2
9
10
27
30
7

4
3
8
84
85
1
−4
12
8
12
22
11
−3
6
9
31
36
2
2
0
10
4
19
4
3
9
10
78
75
3

5
3
8
64
59
3
−3
12
8
87
84
4
−2
6
9
121
121
1
3
0
10
176
186
3
4
9
10
71
73
4

6
3
8
66
60
5
−2
12
8
32
24
16
−1
6
9
105
110
1
4
0
10
105
123
2
5
9
10
49
57
7

3
4
8
133
122
1
−1
12
8
79
81
2
0
6
9
26
20
3
−4
1
10
167
184
2
−4
10
10
47
43
3

2
4
8
182
179
5
0
12
8
242
234
3
1
6
9
104
110
2
−3
1
10
153
164
3
−3
10
10
29
35
4

1
4
8
77
64
1
1
12
8
79
82
1
2
6
9
123
122
2
−2
1
10
80
79
1
−2
10
10
137
135
1

0
4
8
60
66
2
2
12
8
24
24
7
3
6
9
35
36
5
−1
1
10
272
278
2
−1
10
10
114
108
1

1
4
8
76
64
3
3
12
8
82
84
5
4
6
9
105
107
1
0
1
10
327
322
4
0
10
10
361
371
4

3
4
8
131
122
1
4
12
8
33
22
14
5
6
9
61
68
7
1
1
10
275
277
4
1
10
10
114
108
2

4
4
8
92
99
4
−3
13
8
39
30
5
6
6
9
19
49
6
2
1
10
78
79
1
2
10
10
138
134
3

5
4
8
77
68
3
−2
13
8
96
96
3
−4
7
9
86
87
3
3
1
10
149
164
4
3
10
10
24
35
11

6
4
8
73
71
4
−1
13
8
50
47
4
−3
7
9
94
94
1
4
1
10
173
183
3
4
10
10
32
43
9

4
5
8
42
38
6
0
13
8
57
45
3
−2
7
9
148
151
1
−4
2
10
167
187
3
−4
11
10
59
58
3

3
5
8
25
21
2
1
13
8
46
47
2
−1
7
9
52
55
1
−3
2
10
85
87
1
−3
11
10
116
120
2

2
5
8
161
158
1
2
13
8
99
96
2
0
7
9
90
87
2
−2
2
10
179
185
3
−2
11
10
74
82
2

1
5
8
136
135
2
3
13
8
33
30
7
1
7
9
52
55
1
−1
2
10
142
143
2
−1
11
10
144
144
1

0
5
8
71
70
4
−3
14
8
27
24
5
2
7
9
155
151
2
0
2
10
203
201
2
0
11
10
189
187
4

1
5
8
129
134
2
−2
14
8
24
25
8
3
7
9
95
95
2
1
2
10
138
143
3
1
11
10
143
144
3

2
11
10
68
81
3
5
6
11
60
74
4
2
2
12
114
111
1
2
11
12
51
48
16
0
7
13
23
18
5

3
11
10
115
120
3
−4
7
11
33
24
5
3
2
12
62
62
1
3
11
12
43
17
6
1
7
13
80
80
1

4
11
10
59
58
5
−3
7
11
130
131
2
4
2
12
57
60
3
4
11
12
27
44
10
2
7
13
110
107
1

4
12
10
28
42
11
−2
7
11
27
22
2
5
2
12
44
50
6
−3
12
12
48
44
9
3
7
13
100
96
3

3
12
10
31
37
5
−1
7
11
84
82
1
−4
3
12
93
92
2
−2
12
12
81
75
3
4
7
13
56
65
5

2
12
10
76
78
2
0
7
11
34
23
2
−3
3
12
33
27
2
−1
12
12
49
47
4
5
7
13
25
39
11

1
12
10
100
97
2
1
7
11
85
82
2
−2
3
12
67
65
2
0
12
12
36
32
5
−4
8
13
45
44
18

0
12
10
59
57
3
2
7
11
23
23
4
−1
3
12
100
103
1
1
12
12
53
47
4
−3
8
13
53
50
3

1
12
10
97
98
1
3
7
11
136
131
2
0
3
12
227
236
2
2
12
12
69
75
3
−2
8
13
88
88
1

2
12
10
72
78
4
4
7
11
34
24
8
1
3
12
103
103
3
3
12
12
49
44
5
−1
8
13
89
88
1

3
12
10
31
37
7
5
7
11
40
54
6
2
3
12
63
65
2
−2
13
12
74
72
5
0
8
13
222
221
1

4
12
10
56
42
5
−4
8
11
39
37
17
3
3
12
24
27
3
−1
13
12
45
37
9
1
8
13
87
88
1

3
13
10
24
26
6
−3
8
11
34
34
4
4
3
12
88
92
2
0
13
12
16
25
15
2
8
13
80
88
2

2
13
10
36
39
4
−2
8
11
45
41
2
5
3
12
89
104
3
1
13
12
23
37
8
3
8
13
48
51
6

1
13
10
59
51
2
−1
8
11
184
185
4
−4
4
12
59
64
5
2
13
12
62
72
8
4
8
13
45
44
6

0
13
10
43
51
4
0
8
11
34
31
2
−3
4
12
81
82
1
−1
14
12
24
24
9
−4
9
13
54
42
3

1
13
10
50
51
2
1
8
11
186
185
1
−2
4
12
66
63
1
0
14
12
48
54
3
−3
9
13
66
69
7

2
13
10
28
40
8
2
8
11
40
41
2
−1
4
12
66
67
1
1
14
12
19
24
18
−2
9
13
48
52
2

3
13
10
24
26
23
3
8
11
17
34
16
0
4
12
59
63
1
1
0
13
92
83
2
−1
9
13
30
21
8

2
14
10
36
30
4
4
8
11
45
37
6
1
4
12
70
67
1
2
0
13
37
37
2
0
9
13
58
95
1

1
14
10
48
52
3
5
8
11
20
27
20
2
4
12
64
63
3
3
0
13
205
205
2
1
9
13
34
21
5

0
14
10
56
55
3
−4
9
11
42
45
11
3
4
12
79
82
2
4
0
13
48
49
3
2
9
13
53
52
3

1
14
10
39
52
7
−3
9
11
122
123
1
4
4
12
51
64
4
−5
1
13
35
9
10
3
9
13
62
69
5

2
14
10
39
30
5
−2
9
11
88
86
1
5
4
12
28
41
10
−4
1
13
183
182
3
4
9
13
38
42
7

1
15
10
27
18
6
−1
9
11
145
144
1
−4
5
12
78
90
8
−3
1
13
88
88
2
−4
10
13
50
53
4

0
15
10
28
39
13
0
9
11
41
42
2
−3
5
12
30
33
3
−2
1
13
96
97
3
−3
10
13
70
76
3

1
0
11
76
85
2
1
9
11
141
144
1
−2
5
12
115
116
2
−1
1
13
164
167
2
−2
10
13
37
30
3

2
0
11
48
59
2
2
9
11
88
86
4
−1
5
12
32
29
2
0
1
13
109
106
1
−1
10
13
76
76
1

3
0
11
189
196
2
3
9
11
129
123
3
0
5
12
135
139
1
1
1
13
164
167
3
0
10
13
101
102
1

4
0
11
89
91
2
4
9
11
43
45
6
1
5
12
38
29
2
2
1
13
98
97
2
1
10
13
72
76
2

4
1
11
95
94
2
−4
10
11
31
34
13
2
5
12
112
116
2
3
1
13
87
88
1
2
10
13
27
30
8

3
1
11
158
159
4
−3
10
11
85
81
1
3
5
12
30
33
5
4
1
13
169
182
2
3
10
13
65
76
3

2
1
11
64
61
2
−2
10
11
118
109
2
4
5
12
81
90
3
−5
2
13
74
32
5
4
10
13
51
53
5

1
1
11
199
192
4
−1
10
11
32
33
4
5
5
12
16
35
16
−4
2
13
31
32
10
−3
11
13
21
19
20

0
1
11
50
42
5
0
10
11
303
302
2
−4
6
12
92
91
4
−3
2
13
44
41
2
−2
11
13
100
98
1

1
1
11
194
192
2
1
10
11
36
33
2
−3
6
12
42
45
4
−2
2
13
95
96
2
−1
11
13
32
30
3

2
1
11
68
60
1
2
10
11
112
110
5
−2
6
12
38
33
2
−1
2
13
141
145
1
0
11
13
90
85
3

3
1
11
155
159
4
3
10
11
77
80
3
−1
6
12
85
86
1
0
2
13
68
61
1
1
11
13
38
30
4

4
1
11
92
94
2
4
10
11
35
34
7
0
6
12
116
120
1
1
2
13
140
145
1
2
11
13
102
98
2

4
2
11
100
104
3
−4
11
11
43
48
6
1
6
12
86
85
1
2
2
13
101
96
1
3
11
13
25
19
11

3
2
11
23
14
10
−3
11
11
40
42
3
2
6
12
33
34
2
3
2
13
43
41
2
−2
12
13
25
24
6

2
2
11
98
95
2
−2
11
11
70
67
2
3
6
12
50
45
4
4
2
13
36
32
4
−1
12
13
35
35
3

1
2
11
279
296
4
−1
11
11
107
103
1
4
6
12
87
91
3
5
2
13
29
31
13
0
12
13
86
90
5

0
2
11
183
186
8
0
11
11
24
4
11
5
6
12
13
30
12
−4
3
13
61
61
4
1
12
13
29
35
20

1
2
11
287
296
3
1
11
11
104
103
1
−4
7
12
54
48
10
−3
3
13
35
22
11
2
12
13
15
24
14

2
2
11
97
95
1
2
11
11
66
67
3
−3
7
12
81
78
1
−2
3
13
96
96
2
3
12
13
40
33
6

3
2
11
17
15
5
3
11
11
33
42
21
−2
7
12
162
158
1
−1
3
13
88
89
1
−1
13
13
48
50
3

4
2
11
102
104
2
4
11
11
39
47
6
−1
7
12
110
108
1
0
3
13
163
158
1
0
13
13
24
4
10

4
3
11
74
74
2
−3
12
11
25
18
25
0
7
12
65
66
2
1
3
13
90
88
2
1
13
13
41
50
4

3
3
11
117
117
2
−2
12
11
76
77
5
1
7
12
111
108
1
2
3
13
96
96
1
0
0
14
92
95
2

2
3
11
46
48
3
−1
12
11
66
64
3
2
7
12
154
158
4
3
3
13
24
21
3
1
0
14
78
71
1

1
3
11
23
19
2
0
12
11
25
18
10
3
7
12
78
78
3
4
3
13
51
61
4
2
0
14
118
114
1

0
3
11
126
134
3
1
12
11
62
64
3
4
7
12
44
48
5
5
3
13
54
62
5
3
0
14
119
124
2

1
3
11
25
20
2
2
12
11
77
77
10
5
7
12
25
32
10
−4
4
13
76
80
6
4
0
14
102
97
2

2
3
11
47
47
1
3
12
11
22
18
18
−4
8
12
68
72
4
−3
4
13
56
49
2
5
0
14
43
71
8

3
3
11
112
117
3
−3
13
11
49
56
6
−3
8
12
71
67
2
−2
4
13
55
57
1
−5
1
14
31
29
10

4
3
11
73
74
3
−2
13
11
53
55
4
−2
8
12
87
84
1
−1
4
13
75
71
1
−4
1
14
36
44
3

5
3
11
45
52
5
−1
13
11
27
20
6
−1
8
12
90
89
1
0
4
13
18
19
3
−3
1
14
35
33
4

4
4
11
65
66
2
0
13
11
50
40
6
0
8
12
66
60
2
1
4
13
77
72
2
−2
1
14
23
8
4

3
4
11
189
186
3
1
13
11
36
20
8
1
8
12
90
89
1
2
4
13
59
58
2
−1
1
14
60
60
2

2
4
11
26
24
3
2
13
11
40
55
12
2
8
12
85
84
2
3
4
13
54
49
2
0
1
14
85
81
1

1
4
11
101
100
1
3
13
11
55
56
7
3
8
12
72
67
4
4
4
13
72
80
3
1
1
14
57
61
1

0
4
11
79
83
1
−2
14
11
25
13
7
4
8
12
66
72
5
5
4
13
24
32
11
2
1
14
22
7
3

1
4
11
101
100
1
−1
14
11
26
28
10
5
8
12
13
26
12
−4
5
13
37
38
4
3
1
14
38
33
5

2
4
11
26
24
5
0
14
11
36
41
4
−4
9
12
94
92
2
−3
5
13
80
79
2
4
1
14
38
44
4

3
4
11
185
186
3
1
14
11
18
28
17
−3
9
12
113
114
2
−2
5
13
81
79
1
5
1
14
4
28
4

4
4
11
63
66
3
2
14
11
27
14
7
−2
9
12
21
25
4
−1
5
13
26
26
2
−5
2
14
76
84
4

5
4
11
47
52
5
0
0
12
640
627
11
−1
9
12
112
107
2
0
5
13
266
274
2
−4
2
14
75
78
2

4
5
11
17
12
8
1
0
12
27
27
2
0
9
12
58
52
1
1
5
13
32
26
4
−3
2
14
215
215
7

3
5
11
106
101
4
2
0
12
153
155
1
1
9
12
109
107
2
2
5
13
84
79
2
−2
2
14
79
79
2

2
5
11
98
100
1
3
0
12
93
99
3
2
9
12
20
25
6
3
5
13
78
79
3
−1
2
14
152
146
1

1
5
11
136
133
2
4
0
12
110
113
2
3
9
12
107
114
3
4
5
13
39
38
6
0
2
14
19
1
4

0
5
11
78
75
1
−4
1
12
191
207
3
4
9
12
84
92
4
5
5
13
53
60
5
1
2
14
151
146
3

1
5
11
134
133
2
−3
1
12
150
158
3
−4
10
12
26
25
7
−4
6
13
81
88
8
2
2
14
84
79
1

2
5
11
94
101
2
−2
1
12
42
37
2
−3
10
12
33
13
13
−3
6
13
44
36
5
3
2
14
212
215
1

3
5
11
105
101
2
−1
1
12
132
137
2
−2
10
12
71
68
2
−2
6
13
111
110
1
4
2
14
73
78
2

4
5
11
30
12
6
0
1
12
130
121
1
−1
10
12
72
72
1
−1
6
13
143
140
1
5
2
14
54
84
5

5
5
11
46
42
6
1
1
12
131
137
1
0
10
12
161
162
2
0
6
13
23
11
3
−5
3
14
52
44
6

4
6
11
74
73
2
2
1
12
38
37
3
1
10
12
70
71
2
1
6
13
142
140
2
−4
3
14
33
39
5

3
6
11
63
60
3
3
1
12
145
157
4
2
10
12
71
69
2
2
6
13
112
110
1
−3
3
14
49
48
2

2
6
11
34
33
3
4
1
12
197
207
3
3
10
12
15
13
15
3
6
13
47
36
5
−2
3
14
57
50
5

1
6
11
141
145
1
−4
2
12
60
60
2
4
10
12
14
25
14
4
6
13
76
88
3
−1
3
14
83
81
1

0
6
11
47
30
3
−3
2
12
60
61
2
−3
11
12
32
17
9
5
6
13
24
44
11
0
3
14
63
65
1

1
6
11
142
145
2
−2
2
12
115
112
1
−2
11
12
46
48
5
−4
7
13
55
64
3
1
3
14
84
82
3

2
6
11
32
33
2
−1
2
12
192
198
2
−1
11
12
56
51
3
−3
7
13
100
95
2
2
3
14
54
50
1

3
6
11
60
60
3
0
2
12
104
106
1
0
11
12
35
26
4
−2
7
13
110
107
2
3
3
14
53
48
3

4
6
11
66
72
4
1
2
12
195
198
2
1
11
12
48
51
3
−1
7
13
80
80
2
4
3
14
31
39
8

5
3
14
26
44
11
2
1
15
160
151
2
1
11
15
25
20
8
−2
10
16
73
78
4
1
0
18
129
120
2

5
4
14
46
21
6
3
1
15
136
131
1
2
11
15
6
38
5
−1
10
16
25
23
6
2
0
18
197
195
2

4
4
14
23
12
8
4
1
15
49
57
5
−1
12
15
35
41
6
0
10
16
25
13
7
3
0
18
23
20
11

3
4
14
54
43
5
5
1
15
35
56
11
0
12
15
42
42
4
1
10
16
21
23
9
−4
1
18
48
50
4

2
4
14
34
19
3
−4
2
15
47
46
4
1
12
15
42
41
5
2
10
16
72
78
5
−3
1
18
44
41
4

1
4
14
49
46
1
−3
2
15
38
35
3
0
0
16
27
8
3
−1
11
16
28
13
12
−2
1
18
88
80
2

0
4
14
54
52
2
−2
2
15
42
37
3
1
0
16
70
62
1
0
11
16
30
13
5
−1
1
18
52
49
2

1
4
14
53
46
2
−1
2
15
170
165
1
2
0
16
31
18
3
1
11
16
17
14
17
0
1
18
26
23
4

2
4
14
28
19
6
0
2
15
166
157
2
3
0
16
91
95
1
0
12
16
29
18
7
1
1
18
56
49
2

3
4
14
45
43
3
1
2
15
172
165
3
4
0
16
13
12
12
1
0
17
19
2
5
2
1
18
83
80
3

5
4
14
31
21
7
2
2
15
41
37
4
−4
1
16
60
73
3
2
0
17
82
71
3
3
1
18
40
41
6

4
5
14
33
43
5
3
2
15
33
36
3
−3
1
16
64
62
2
3
0
17
78
73
2
4
1
18
33
50
6

3
5
14
59
49
3
4
2
15
38
46
5
−2
1
16
133
123
1
4
0
17
15
27
15
−4
2
18
34
39
14

2
5
14
29
23
3
5
2
15
45
37
9
−1
1
16
105
101
1
−4
1
17
30
32
5
−3
2
18
17
3
14

1
5
14
52
50
1
−5
3
15
60
57
5
0
1
16
32
20
3
−3
1
17
28
32
6
−2
2
18
135
126
1

0
5
14
27
30
3
−4
3
15
39
45
3
1
1
16
109
101
3
−2
1
17
150
139
1
−1
2
18
54
47
2

1
5
14
57
50
4
−3
3
15
47
36
3
2
1
16
131
123
1
−1
1
17
114
111
1
0
2
18
23
20
6

2
5
14
37
23
11
−2
3
15
134
131
2
3
1
16
60
62
4
0
1
17
26
1
7
1
2
18
52
47
2

3
5
14
56
50
2
−1
3
15
75
75
1
4
1
16
71
73
3
1
1
17
118
111
1
2
2
18
137
126
3

4
5
14
40
42
6
0
3
15
180
165
1
−4
2
16
55
59
4
2
1
17
147
139
2
3
2
18
19
3
19

4
6
14
58
57
3
1
3
15
78
74
1
−3
2
16
64
58
3
3
1
17
28
32
5
4
2
18
20
39
20

3
6
14
97
96
2
2
3
15
133
131
1
−2
2
16
69
61
1
4
1
17
37
32
7
−4
3
18
43
29
7

2
6
14
104
102
1
3
3
15
33
36
3
−1
2
16
152
147
1
−4
2
17
35
33
4
−3
3
18
25
5
6

1
6
14
42
41
2
4
3
15
40
46
6
0
2
16
36
22
2
−3
2
17
42
22
4
−2
3
18
63
57
2

0
6
14
21
8
4
5
3
15
43
57
6
1
2
16
153
147
3
−2
2
17
87
78
2
−1
3
18
29
23
4

1
6
14
42
41
2
−5
4
15
32
8
10
2
2
16
66
61
1
−1
2
17
63
60
1
0
3
18
54
53
4

2
6
14
106
102
1
−4
4
15
41
33
8
3
2
16
57
58
4
0
2
17
28
16
5
2
3
18
49
57
3

3
6
14
86
96
3
−3
4
15
80
81
4
4
2
16
45
59
4
1
2
17
60
60
3
3
3
18
16
4
15

4
6
14
54
56
5
−2
4
15
93
94
3
−4
3
16
40
46
9
2
2
17
87
79
3
4
3
18
27
29
18

4
7
14
73
82
9
−1
4
15
24
16
3
−3
3
16
64
59
2
3
2
17
23
22
7
−3
4
18
14
4
14

3
7
14
32
34
7
0
4
15
90
92
1
−2
3
16
25
16
3
4
2
17
20
33
19
−2
4
18
52
45
3

2
7
14
61
65
1
1
4
15
38
16
4
−1
3
16
137
133
1
−4
3
17
30
11
6
−1
4
18
35
33
3

1
7
14
176
179
1
2
4
15
96
94
5
0
3
16
36
20
2
−3
3
17
70
67
4
0
4
18
48
47
2

0
7
14
25
5
3
3
4
15
84
81
2
1
3
16
137
133
3
−2
3
17
57
46
2
1
4
18
42
32
4

1
7
14
181
179
2
4
4
15
25
33
12
2
3
16
24
17
12
−1
3
17
55
55
1
2
4
18
58
45
3

2
7
14
63
65
2
−4
5
15
45
33
4
3
3
16
59
59
3
0
3
17
40
28
3
4
4
18
31
44
10

3
7
14
29
34
10
−3
5
15
60
64
2
4
3
16
40
46
7
1
3
17
58
55
3
−3
5
18
43
35
3

4
7
14
73
81
4
−2
5
15
123
127
1
−4
4
16
41
38
10
2
3
17
54
46
4
−2
5
18
52
43
5

4
8
14
31
26
7
−1
5
15
46
48
1
−3
4
16
58
55
2
3
3
17
60
66
2
−1
5
18
53
49
3

3
8
14
50
65
3
0
5
15
116
109
2
−2
4
16
104
97
1
−4
4
17
39
38
5
0
5
18
52
48
2

2
8
14
72
69
2
1
5
15
50
48
2
−1
4
16
80
75
1
−3
4
17
46
43
3
1
5
18
53
49
5

1
8
14
71
68
1
2
5
15
124
127
2
0
4
16
47
42
2
−2
4
17
60
57
3
2
5
18
46
43
3

0
8
14
102
107
1
3
5
15
59
64
3
1
4
16
81
75
2
−1
4
17
88
90
1
3
5
18
36
35
8

1
8
14
70
68
3
4
5
15
4
33
4
2
4
16
105
97
3
0
4
17
12
5
11
−3
6
18
23
32
7

2
8
14
71
69
2
−4
6
15
43
36
7
3
4
16
54
54
4
1
4
17
89
90
2
−2
6
18
65
66
3

3
8
14
59
64
5
−3
6
15
38
39
7
4
4
16
27
38
9
2
4
17
55
57
2
−1
6
18
41
37
4

4
8
14
4
26
4
−2
6
15
76
73
1
−4
5
16
41
38
4
3
4
17
44
43
7
0
6
18
8
1
8

4
9
14
26
27
25
−1
6
15
112
121
1
−3
5
16
26
9
7
4
4
17
24
38
13
1
6
18
27
37
8

3
9
14
37
11
5
0
6
15
58
57
2
−2
5
16
78
79
1
−4
5
17
52
49
3
2
6
18
62
66
2

2
9
14
62
66
3
1
6
15
116
121
2
−1
5
16
41
41
2
−3
5
17
43
36
4
−3
7
18
25
17
10

1
9
14
60
59
2
2
6
15
70
73
2
0
5
16
84
88
1
−2
5
17
42
39
4
−2
7
18
45
38
3

0
9
14
34
28
3
3
6
15
33
39
8
1
5
16
44
40
2
−1
5
17
113
109
1
−1
7
18
30
17
5

1
9
14
57
59
2
4
6
15
17
36
16
2
5
16
78
79
2
0
5
17
70
68
2
0
7
18
42
45
15

2
9
14
69
66
2
−4
7
15
43
39
5
3
5
16
25
9
8
1
5
17
113
109
2
1
7
18
31
17
19

4
9
14
16
27
16
−3
7
15
33
31
12
4
5
16
26
38
10
2
5
17
36
39
4
2
7
18
36
38
3

3
10
14
39
37
4
−2
7
15
83
78
2
−4
6
16
45
23
10
3
5
17
31
36
4
−2
8
18
52
51
3

2
10
14
37
37
4
−1
7
15
38
29
5
−3
6
16
63
66
2
4
5
17
38
49
6
−1
8
18
61
61
3

1
10
14
46
43
2
0
7
15
54
45
3
−2
6
16
17
14
17
−3
6
17
45
7
5
0
8
18
55
65
3

0
10
14
72
75
2
1
7
15
44
29
8
−1
6
16
64
64
1
−2
6
17
26
17
6
1
8
18
55
61
9

1
10
14
45
43
5
2
7
15
79
78
2
0
6
16
77
80
1
−1
6
17
56
54
2
2
8
18
47
51
3

2
10
14
33
37
4
3
7
15
6
31
5
1
6
16
69
64
2
0
6
17
65
56
3
−1
9
18
39
41
5

3
10
14
43
37
6
4
7
15
36
39
7
2
6
16
21
14
7
1
6
17
60
53
3
0
9
18
16
12
13

3
11
14
27
19
9
−4
8
15
35
32
6
3
6
16
68
66
5
2
6
17
23
17
22
1
9
18
42
41
6

2
11
14
54
48
3
−3
8
15
48
53
6
4
6
16
9
23
9
3
6
17
18
7
18
1
0
19
15
6
15

1
11
14
51
53
3
−2
8
15
28
37
5
−4
7
16
28
3
7
−3
7
17
57
58
3
2
0
19
29
24
9

0
11
14
78
75
2
−1
8
15
47
42
4
−3
7
16
50
41
3
−2
7
17
96
98
2
3
0
19
37
25
20

1
11
14
53
53
4
0
8
15
120
122
2
−2
7
16
74
76
2
−1
7
17
58
62
4
−3
1
19
63
66
2

2
11
14
50
48
4
1
8
15
49
42
2
−1
7
16
96
97
2
0
7
17
97
96
5
−2
1
19
48
54
3

2
12
14
32
30
4
2
8
15
40
37
20
0
7
16
67
69
3
1
7
17
58
61
3
−1
1
19
53
52
4

1
12
14
69
71
2
3
8
15
58
53
5
1
7
16
98
97
2
2
7
17
92
98
3
0
1
19
17
8
12

0
12
14
22
4
8
−3
9
15
73
79
2
2
7
16
73
76
5
3
7
17
64
58
4
1
1
19
54
52
3

1
12
14
70
71
4
−2
9
15
37
39
5
3
7
16
25
41
13
−3
8
17
50
51
3
2
1
19
52
54
5

2
12
14
34
30
10
−1
9
15
55
53
6
4
7
16
4
3
4
−2
8
17
78
82
2
3
1
19
59
66
2

1
13
14
33
39
5
0
9
15
36
27
4
−3
8
16
62
61
2
−1
8
17
31
32
8
−3
2
19
36
50
4

0
13
14
28
28
8
1
9
15
59
53
3
−2
8
16
33
24
4
0
8
17
31
12
11
−2
2
19
48
34
3

1
13
14
15
39
14
2
9
15
41
39
7
−1
8
16
75
73
6
1
8
17
18
32
18
−1
2
19
34
29
4

1
0
15
309
302
3
3
9
15
63
79
9
0
8
16
48
51
4
2
8
17
83
82
6
0
2
19
29
12
7

2
0
15
63
62
1
−3
10
15
45
45
4
1
8
16
72
73
2
3
8
17
41
51
6
1
2
19
19
29
10

3
0
15
21
13
19
−2
10
15
21
22
7
2
8
16
28
24
5
−2
9
17
49
54
3
2
2
19
34
34
6

4
0
15
37
38
5
−1
10
15
59
48
3
3
8
16
62
62
4
−1
9
17
44
37
4
3
2
19
42
50
8

5
1
15
48
57
5
0
10
15
17
15
12
−3
9
16
23
28
8
0
9
17
35
1
9
−3
3
19
29
14
6

4
1
15
52
57
3
1
10
15
46
48
3
−2
9
16
43
47
3
1
9
17
36
37
4
−2
3
19
35
24
4

3
1
15
138
130
3
2
10
15
24
22
7
−1
9
16
48
39
3
2
9
17
55
54
2
−1
3
19
45
39
3

2
1
15
161
151
2
3
10
15
32
44
6
0
9
16
30
42
5
−1
10
17
27
21
4
0
3
19
35
33
7

1
1
15
102
95
1
−2
11
15
39
38
3
1
9
16
42
39
3
0
10
17
22
2
10
1
3
19
30
39
5

0
1
15
93
90
1
−1
11
15
33
20
4
2
9
16
40
47
3
1
10
17
18
21
12
2
3
19
41
24
4

1
1
15
101
95
2
0
11
15
22
21
8
3
9
16
26
28
12
0
0
18
27
7
6
−3
4
19
24
19
10

2
4
19
53
54
2
2
7
19
13
15
12
0
2
20
34
10
13
2
5
20
21
25
6
2
2
21
36
32
16

1
4
19
33
31
3
−1
8
19
57
58
3
1
2
20
27
41
7
−2
6
20
30
18
8
−2
3
21
39
37
6

0
4
19
50
51
4
0
8
19
43
41
4
2
2
20
71
71
3
−1
6
20
28
26
5
−1
3
21
37
17
6

1
4
19
20
31
10
1
8
19
54
58
13
3
2
20
46
47
6
0
6
20
20
5
11
1
3
21
25
17
7

2
4
19
46
54
5
0
0
20
41
45
5
−3
3
20
58
58
3
1
6
20
33
26
6
2
3
21
33
37
11

2
5
19
38
27
7
1
0
20
131
131
3
−2
3
20
39
37
4
0
7
20
21
2
15
−1
4
21
14
19
14

1
5
19
20
10
9
2
0
20
46
36
4
−1
3
20
31
33
4
1
7
20
13
7
12
0
4
21
41
29
5

0
5
19
19
18
11
3
0
20
30
9
7
0
3
20
29
20
9
1
0
21
45
43
4
0
5
21
29
15
14

2
5
19
33
28
10
−3
1
20
38
13
8
1
3
20
41
33
4
2
0
21
33
28
7
1
5
21
10
14
9

2
6
19
29
29
6
−2
1
20
63
65
4
2
3
20
36
37
3
−2
1
21
61
69
6
0
0
22
24
49
4

1
6
19
19
20
18
−1
1
20
34
37
5
−2
4
20
40
34
3
−1
1
21
50
51
6
1
0
22
44
35
5

0
6
19
29
12
6
0
1
20
38
43
3
−1
4
20
53
47
4
0
1
21
21
19
6
−1
1
22
39
31
6

1
6
19
31
20
5
1
1
20
32
37
6
0
4
20
31
30
4
1
1
21
61
51
3
0
1
22
27
13
6

2
6
19
22
29
8
2
1
20
65
65
6
1
4
20
57
47
9
2
1
21
55
69
4
1
1
22
21
31
20

2
7
19
34
15
10
3
1
20
34
13
9
2
4
20
26
34
5
−2
2
21
27
32
7
0
2
22
35
37
6

1
7
19
16
23
15
−3
2
20
46
47
10
−2
5
20
30
25
8
−1
2
21
44
47
3

0
7
19
27
20
15
−2
2
20
72
71
2
−1
5
20
27
20
6
0
2
21
28
24
5

1
7
19
32
23
5
−1
2
20
40
41
3
0
5
20
18
18
17
1
2
21
45
47
5

SYNTHESIS OF 2MBP

EXAMPLE 3

[0029] The preparation of 2MBP having the basic structure I can be accomplished by a common general method, i.e. the condensation of a bicyclic Windaus-Grundmann type ketone II with the allylic phosphine oxide III to the corresponding 2-methylene-19-nor-vitamin D analog IV followed by deprotection at C-1 and C-3 in the latter compound IV to obtain compound I, i.e. 2MBP.

[0030] In the structures II, III, and IV groups Y1 and Y2 are hydroxy-protecting groups, it being also understood that any functionalities that might be sensitive, or that interfere with the condensation reaction, be suitably protected as is well-known in the art. The process shown above represents an application of the convergent synthesis concept, which has been applied effectively for the preparation of vitamin D compounds [e.g. Lythgoe et al., J. Chem. Soc. Perkin Trans. 1, 590 (1978); Lythgoe, Chem. Soc. Rev. 9, 449 (1983); Toh et al., J. Org. Chem. 48, 1414 (1983); Baggiolini et al., J. Org. Chem. 51, 3098 (1986); Sardina et al., J. Org. Chem. 51, 1264 (1986); J. Org. Chem. 51, 1269 (1986); DeLuca et al., U.S. Pat. No. 5,086,191; DeLuca et al., U.S. Pat. No. 5,536,713].

[0031] Hydrindanones of the general structure II are known, or can be prepared by known methods.

[0032] For the preparation of the required phosphine oxides of general structure III, a synthetic route has been developed starting from a methyl quinicate derivative which is easily obtained from commercial (1R,3R,4S,5R)-(−)-quinic acid as described by Perlman et al., Tetrahedron Lett. 32, 7663 (1991) and DeLuca et al., U.S. Pat. No. 5,086,191.

[0033] The overall process of the synthesis of compound I is illustrated and described more completely in U.S. Pat. No. 5,843,928 entitled “2-Alkylidene-19-Nor-Vitamin D Compounds” and in application Ser. No. 09/878,438 filed Jun. 11, 2001 entitled “1α-Hydroxy-2-Methylene-19-Nor-Homopregnacalciferol and its Uses” the specifications of which are specifically incorporated herein by reference.

[0034] As used in the description and in the claims, the term “hydroxy-protecting group” signifies any group commonly used for the temporary protection of hydroxy functions, such as for example, alkoxycarbonyl, acyl, alkylsilyl or alkylarylsilyl groups (hereinafter referred to simply as “silyl” groups), and alkoxyalkyl groups. Alkoxycarbonyl protecting groups are alkyl-O-CO- groupings such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl or allyloxycarbonyl. The term “acyl” signifies an alkanoyl group of 1 to 6 carbons, in all of its isomeric forms, or a carboxyalkanoyl group of 1 to 6 carbons, such as an oxalyl, malonyl, succinyl, glutaryl group, or an aromatic acyl group such as benzoyl, or a halo, nitro or alkyl substituted benzoyl group. The word “alkyl” as used in the description of the claims, denotes a straight-chain or branched alkyl radical of 1 to 10 carbons, in all its isomeric forms. Alkoxyalkyl protecting groups are groupings such as methoxymethyl, ethoxymethyl, methoxyethoxymethyl, or tetrahydrofuranyl and tetrahydropyranyl. Preferred silyl-protecting groups are trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, dibutylmethylsilyl, diphenylmethylsilyl, phenyldimethylsilyl, diphenyl-t-butylsilyl and analogous alkylated silyl radicals. The term “aryl” specifies a phenyl-, or an alkyl-, nitro- or halo-substituted phenyl group.

[0035] A “protected hydroxy” group is a hydroxy group derivatised or protected by any of the above groups commonly used for the temporary or permanent protection of hydroxy functions, e.g. the silyl, alkoxyalkyl, acyl or alkoxycarbonyl groups, as previously defined. The terms “hydroxyalkyl”, “deuteroalkyl”, “aminoalkyl”, “halogenalkyl”, “alkoxyalkyl”, “aryloxyalkyl”, and “fluoroalkyl” refer to an alkyl radical substituted by one or more hydroxy, deuterium, amino, halogen, alkoxy, aryloxy, or fluoro group respectively. A “halogen” group includes any of the five elements fluorine, chlorine, bromine, iodine and astatine that form a part of group VIIA of the periodic table.

[0036] Referring now to Schemes I-III, there are illustrated three different methods of synthesizing 2MBP starting with vitamin D2. The first five steps are identical (shown in Scheme I) for each synthesis to obtain the protected 20(S)-aldehyde. Thereafter, in Schemes I and II the aldehyde is converted to a protected 20(S)-alcohol which in turn has its side chain converted to bis-homo in two different ways (Scheme I versus Scheme II). In contrast, Scheme III illustrates a direct conversion of the protected 20(S)-aldehyde to the bis-homo side chain.

2-Methylene-19-nor-20(S)-1alpha-hydroxy-bis-homo-pregnacalciferol in crystalline form

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Provisional Applications (1)