AU704409B2 - 4,5-bis(aminomethyl and azidomethyl)-1,3-dioxolane intermediates useful for the preparation of platinum (II) complexes - Google Patents

Description

THIS INVENTION relates to novel intermediates useful for the preparation of the platinum (II) complexes which are the subject of Australian Patent Application No. 91247/91. The present invention has been divided from the specification of the aforementioned application, the contents of which are incorporated herein by reference.

According to one aspect of the present invention there is provided a 4 ,5-bis(aminomethyl)-1,3-dioxolane compound of the formula R1 0 NH2 Rz 0 NH2 wherein R, and R 2 are the same or different and are selected from the group 15 consisting of a hydrogen atom and a C, C, alkyl group, or together form a cycloalkane group with the carbon atom attached thereto, with the proviso that R, and R 2 are not simultaneously methyl; and wherein the absolute configurations at the respective chiral centres in the 4 ,5-bis(aminomethyl)-1,3-dioxolane moiety are or According to another aspect of the present invention there is provided a process for preparing the compounds of formula (10) which comprises reducing a 4 ,5-bis(azidomethyl)-1,3-dioxolane of formula with hydrogen in the presence of palladium charcoal or platinum (II) oxide in an alcoholic medium under a pressure of between 0 and 70 psi and a temperature of between 0 and 25 for from 30 minutes to 1 day, Ri 0 N3 R2 0 N3 wherein R, R 2 and the absolute configurations are the same as in formula the said compound of formula being prepared by reacting a 1,3-dioxolane-4,5-bis(methanesulfonate) of formula with an azide ion in N N-dimethylformamide at a temperature of between 20 and 120 0 C for from 1 to 24 hours, Ri 0 -SOzCHJ 0 3 (8) R2 0 SOCH3 wherein

R

2 and the absolute configurations are the same as in formula Preferred embodiments of the invention will now be described it he succeeeding Preparative Examples.

Preparative Example 1: Synthesis of (4R,5R)-4,5-bis(azidomethyl)-1,3dioxolane D-threitol 1,4-bis(methanesulfonate) was reacted with formaldehyde and concentrated sulfuric acid as described in J. Med. Chem., 7, 14 (1964) to yield 2,3- 20 0-methylene-D-threitol 1, 4 -bis(methanesulfonate) in 61% yeild.

A mixture of 2 3 -0-methylene-D-threitol 1,4bis-(methanesulfonate) (3.19g, 11.0 mmol) and sodium azide (2.86g, 44.0 mmol) in anhydrous ml) was heated at 100 0 C for 16 hours under a nitrogen atmosphere. The reaction mixture was cooled to a room temperature, diluted with water (20 ml) and extracted .with ether (100ml). The ethereal solution was washed with brine (20ml), dried over anhydrous magnesium sulfate and evaporated to dryness under a reduced pressure. The crude product was purified by using flash column chromatography over silica gel with amixture of etherhexane v/v) as the eluent to give 1.93 g of (4R,5R)-4,5-bis(azidomethyl)-1,3-dioxolane as a light yellow oil.

Yield: +125.2\ (acetone) IR (neat) 2103 cm- 1

(N

3 'H NMR(CDC1 3 6 3.30-3.62(m, 4 H, 2 CH 2 3 9 1-4.09(m, 2 H, 2CH), 5.08(s, 2 H, OCH 2

O)

3 C NMR(CDC13): 6 51.64, 77.14, 95.37 Synthesis of 4 ,5i )-4,5-bis(aminomethyl)-1,3-dioxolane A solution of 4 R,5B)-4,5-bis(azidomethyl)-1,3-dioxolane (1.93 g, 10.5 mmol) in ethanol (20 ml) was hydrogenated in the presence of 10% palladium on activated carbon (0.2 g) at 50 psi at 40'C for 2 hours. The reaction mixture was filtered through a pad of celite and evaporated to dryness under a reduced pressure to give 1.35 g of 4 R,5R)- 4 ,5-bis(aminomethyl)-1,3-dioxolane as a colorless oil.

Yield: 97% IR (neat): 3370, 3307 cm-' (NH 2 'H NMR(CDC1 3 6 1.40 4 H, 2 NH2), 2.81-2.98 (in, 4 H, 2 CH2), 3.63-3.82 (in, 2 H, 2 CH), 5.01(s, 2 H, OCH 2 0) 3 C NR(CDC 3 8 43.81, 80.34, 94.34 Preparative Example 2: Synthesis of 4 ,5 )-4,5-bis(azidomethyl)- 1,3-dioxolane L-threitol 1,4-bis(methanesulfonate) was reacted with formaldehyde 5 and concentrated sulfuric acid as described in J. Med. Chem., 7, 14 (1964) to yield 2 3 -O-methylene-L-threitol 1,4-bis(methanesulfonate) in 63% yield.

3.89 g of 2 3 -0-methylene-L-threitol 1,4-bis(methanesulfonate) was reacted with sodium azide in the same maimer as described in Preparative Example 1 to give 2.38 g of 4 S$)-4,5-bis(azidomethyl)-1,3-dioxolane.

Yield: 96% -122.01- (acetone) Synthesis of 4 S,5 4 ,5-bis(aminomethyl)-1,3-dioxolane 1.10 g of 4 S 4 ,5-bis(azidomethyl)-1,3-dioxolane was reduced in the same maimer as described in Preparative Example 1 to give 0.78 g of 4 ,5 )-4,5-bis(aminomethyl)- 1,3-dioxolane.

Yield: 99% Preparative Example 3: Synthesis of 4 R,1 i)- 4 ,5-bis(azidomethyl)-2-methyl- 1,3-dioxolane D-threitol 1,4-bis(methanesulfonate) was reacted with acetaldehye diethyl acetal and methanesulfonic acid as described in J. Med. Chem., 7, 14 (1964) to yield 2,3--O-ethylidene-D-threitol 1,4-bis(methanesulfonate) in yield.

4.28 g of 2,3-O-ethylidene-D-thrcitol 1,4-bis(methanesulfonate) was reacted with sodium azide in the same manner as described in Preparative Example 1 to give 2.59 g of (4!,5ig)-4,5-bis(azidomethyl)-2-methyl-.4,3dioxolane as a light yellow oil.

Yield: 93% 143.800 (acetone) 15 IR(neat): 2101cm-' (N 3 'H NMR (CDC1 3 6 1.42(d, J 4.8 Hz, 3 H, CH 3 3.24-3.63 (in, 4 H, 2 CH 2 3.93-4.13(m, 2 H, 2 CH), 5.24 J=4.8 Hz, 1 H, CH) 1 3 C NMR(CDC1 3 6 19.84, 51.76, 76.80, 77.96, 101.97 Synthesis of 4 ,5S)-4,S-bis(aminomethyl)-2-methyl-1,3-dioxolane 2.52 g of 4 ,5E)-4,5-bis(azidomethyl)-2-methy1-1,3-dioxolane was reduced in the same manner as described in Preparative Example 1 to give 1.80 g of 4 ,5B)- 4 ,S-bis(aminomethyl)-2-methyI-1,3-dioxolane as a semi-solid oil.

Yield: 97% IR(neat): 3375, 3304 cn-' (NH 2 'H NMR (CDC1 3 6 1.37(d, J 4.8 Hz, 3 H, CH 3 1.41(s, 4 H, 2 NH2), 2 .65-3.04(m, 4 H, 2CH2), 3.65-3.87 (mn, 2H, 2 CH), 5.16(q, I 4.8 Hz, 1 H, CH) 13C NMR(CDC1 3 8 19.75, 43.76, 44.05, 80.16, 81.09, 100.35 Preparative Example 4: 6 Synthesis of (4S,5 -4,5-bis(azidomethyl)-2-methyl- 1,3-dioxolane L-threitol 1 ,4-bis(methanesulfonate) was reacted with acetaldehyde diethyl acetal and methanesulfonic acid as described in J. Med. Chem., 7, 14 (1964) to yield 2,3-O-ethylidene-L-threitol 1,4-bis(methanesulfonate) in 96% yield.

4.99 g of 2,3-O-ethylidene-L-threitol 1,4-bis(methanesulfonate) was reacted with sodium azide in the same manner as described in Preparative Example 1 to give 3.18 g of (4,55)-4,5-bis(azidomethy)-2-methyl-1,3dioxolane.

Yield: 98% [cL]D 20 -140.70* (acetone) Synthesis of (4S,5$)-4,5-bis(aminomethyl)-2-methyl- 1,3-dioxolane 2.38 g of (4,55)-4,5-bis(azidomethyl)-2-methy1-1,3-dioxolane was reduced in the same manmer as described in Preparative Example 1 to give 1.75 g of (4,5 )-4,5-bis(aminomethyl)-2-methyl- 1,3-dioxolane.

Yield: 99% Preparative-Example Snhsso (4,R-4,5-bis(azidomethyl)-2-ethyl- 1, 3-dioxolane A mixture of D-threitol l,4-bis(methanesulfonate)(1.80 g, mmol), propionaldehyde(O.41 g, 7.1 mmol, 0.51 0TL), anhydrous copper(II) sulfate(l.55 g, 9.7 mmol) and methanesulfonic acid(2 drops) in anhydrous toluene(30 mg was strirred at a room temperature for 16 hours under a nitrogen atmosphere. Anh~ydrous potassium carbonate(0.3 g) was added to the reaction mixture and stirred for an additional 20 minutes. The reaction mixture was filtered, evaporated to dryness and oily residue was crystallized from a mixture of absolute ethanol and acetone to give 1.60 of 2,3-0-propionylidene-D-threitol 1,4-bis(methanesulfonate) as colorless crystals.

Yield: 78% 65.O-65.5*C IR(Nujol): 1357, 1179 cm- 1 (0-SO2) I- NMR(CDCI 3 J 0.96(t, J =7.4 Hz, 3 H, Cl-b), 1.71(dq, J 4.6 Hz, J 7.4 Hz, 2 H, CH2 3 0 9(s, 6 H, 2 SOzCH3), 4 .0 9 4 .29(m, 2 H, 2 CH), 4 3 3(m, 4 H, 2 CII?), 5-07(t, J =4.6 Hz, I H, CH) 13 C NMR(CDC1j3): J 7.59, 26.89, 37.77, 67.78;- 68.0-0, 75.18, 75.73, 106.38 Alternatively, 2 3 -Q-propionylidene-D-threi 0 jj 1,4-bis- (methansulfonate) may be prepared by the following method.

A mixture of D-tartaric acid(50.O0 g, 0.333 mol) and concentrated sulfuric aicd(5 WQ) in absolute ethanol(500 WQ was heated at reflux for 15 hours. The reaction mixture was cooled to a room temperature and to it, aqueous 28% ammonium hydroxide solution(24 eiC) was added, and the mixture was stirred for an additional 30 minutes. The white precipitate was filtered off .and the filtrate was evaporated to dryness to give 56.09 a of diethyl D-tartrate as an oil.

Yield: 82X 11 NMR(CDC13): 6 1.33(tL, J 7. 2 Hz, 6 H, 2 C113 3.28 (hr s, 2 11, 2 OH), 4l.

3 2(q, J 7.2 Hz, 4 11, 2 C}Iz), 4.54(s, 2 H, 2 CH) 1 3 C NMR(CDC.

3 6 14. 07, 62. 36, 7-1. 95, 171.4 7 A mixture of diethyl D-tartrate(4.00 g, 19.4 mmol), propionaldehyde(5.63 g, 96.9 mmol, 6.99 mP), anhydrous copper(II) sulfate(6.19 g, 38.8 mmol) and methanesulfonic acid(3 drops) in anhydrous toluene(60 mg) was stirred at a room temperature for :16 hours under a nitrogen atmosphere. Anhydrous potassium carbonate(O.3og) was added to the reaction mixture and stirred for an additional 20 minutes. The reaction mixture was filtered, evaporated to dryness and the oily residue was purified by using flash column chromatography over silica gel with a mixture of ether-hexane(1:4, v/v) as the eluent to give 3.80 g of diethyl 2 3 -0-propionylidene-D.-tartrate as an oil.

Yield: IR(neat): 1757, 1740 cm- 1

(C=O)

'H N.MR(CDCl 3 S 1.01(t, I= 7.5 Hz, 3 H, GH3), 1.32(t, .j= 7. 2 Hz, 6 H, 2 CH3), 1.81(dq, J 4.5 Hz, !IJ 7 .5 Hz, 2 H, Cli?) 4 2 7(q, 7 7.2 Hz, 2 H, CH2 4.28(q, J 7.2Hz, 2 H, CH2), 4.66(d, J =4.2 Hz, 1 H, CHI), 4.75(d, J= 4.2 Hz, 1 H, CH), 5.23(t, J 4.5Hz, I H, CHi) 3 C NMR(CDC13): LT 7.59, 14.04, 14.07, 26.64, 61.77, 61.79, 77.13, 77.25, 108.39, 169.09, 169.78 A suspension of lithium aluminum hydride(1.03 g, 27.2 mmol) in ether(25 mQ was refluxed for 30 minutes with vigorous stirring. A solution of diethyl 2 3 -Q'-propionylideie- D-tartrate(5.28 g, 21.4 mmol) in ether(lO Wn) was added dropwise without heating over 30 minutes, the heat of reaction causing a gentle refluxing. After additional heating for 5 hours, ethyl acetate(l.1 rdQ) was carefully added, and the reaction mixture was cooled to 0-5*C. After successive cautious additions of water 9 WQ) 4N NaOH(0. 9 Wn. and water(2.8 mQ) the inorganiic precipitate which had formed was removed by filtration, and V. extracted thoroughly with warm ethyl acetate(2 x 40 rnQ ).The 20 combined organic solution were dried over anhydrous hgSO4, evaporated to dryness and purified by using flash column chromatO.7 graphy over silica gel with a mixture of ethyl acetate and hexane V as the eluent to give 2.28g of 2 3 -0-propionylidene-Dthreitol as an oil.

Yield: 66% IR(neat): 3385 cm- 1

(OH)

IH NMlR(CDC13 J 0.98(t, J 7.5 Hz, 3 H, CH3), J. 4.5 Hz, J 7.5 Hz, 2 HI, CH2), 3.34(br s, 2 H, 2 OH), 3.62-3.88(mn, 4 H, 2 CH2), 3.88- 4.05(m, 2 H, 2 CH), 5.05(t, J 4.5-Hz, 1 H,

CH)

13C NMR(CDCl 3 7.75, 27.13, 62.36, 62.46, 78.29, 79.04, 105.63 To a stirred solution of 2 ,3-Q-propionylidene-D-threitoI (2.18 g, 13.4 mmol) in pyridine(10 Wn) was added methanesulfony-l chloride(3.80 d, 33.2 mwol, 2.57 mf) dropwise at 0'C and the mixture was stirred for 16 hours at a room temperature. The reaction mixture was poured into ice-water(20 ind) with vigorous stirring. The resulting precipitate was filtered, washed well with water and dried in vacuo. The crude product was crystallized from absolute ethanol to give 2.81g of 2 3 -O--propionylidene-D-threitoI 1, 4 -bis(methanesulfonate).

Yield: 66% m. p. 65.0-65. IR(nujol): 1357, 1179 cmw'(O-SO2) 1.43 0 of 2 3 -0-propionylidene-D-tlireitoI 1,4-bis(metnanesulfonate) was reacted with sodium azide in the same manner as described in Preparative Example 1 to give 0.88 g of (4R,5R)-'4,5bis(azidomethyl).-2-ethy-l-13dioxolane as a light yellow oil.

Yield: 92x [a 11'0 +127.880 (acetone) IR(neat): 2102 cm- 1

MN)

15 'H NlIR(CDC1 3 J 0.98(t, J =7.5 Hz, 3 H, CH3), 1.72(dq, J =4.5H, 5 H,2 H, CH2 (in, 4 H, 2 CH2 3. 9 7 07(m, 2 H1, 2 CH) 5. 07 t, J 4. 5 Hz, I It, CIO) 1 3 C NMR(CDCI 3 6 7.64, 27.09, 51.88, 51.94, 77.94, 105.86 Synthesis of (4,R-,-i~mnmtyl--ty-,-ixln 0.85 g of 4 R,5R)-4,5-bis(azidomethyl).2..ethyl-13.

dioxolane was reduced in the'same manner as described in Preparative 25 Example I to give 0.61 g of 4 RsSR)- 4 ,5-bis(aminomethy)-2-ethyl.

l, 3 -dioxolane as a semi-solid Oil.

Yield: *IR(neat): 3367 cm- 1 (NH2) 'H NiNIR(CDClj): 6 0.97(t, .J 7.5 Hz, 3 H, CH3), 1.36(s, 4 H, 2 14Hz, 1.68(dq, J 4.5 Hz, J 7.5 Hz, 2 HI, CH2), 2 7 5 3 .00(m, 4 H, 2 CII?), 3 7 0- 3 8 0(mn, 2 H, 2 CH), 5.00(t, J =4.5 Hz, I H, CH) 3 C WNIR(CDC13): 7.83, 27.19, 44.05, 44.33, 80.34, 81.11, 104. 59 Preparative Example 6: Synthesis of .(4S,5S)-4,5-bis(azidome-thy1)-2-ethy1,3dioxolane A mixture of L-threitol l,4-bis(methanesulfonate)(4.OO g 14.4 mmnol), propionaldehyde diethyl acetal(19.OO g, 144.0 mmol, 23.3 mQ) and methanesulfonic acid(2 drops) was heated at 70*C for 16 hours tinder a nitrogen atmosphere. The reaction mixture was cooled to 0'C with an ice bath and diluted with ether(l00 WQ.

After standing for 1 hour at 'C the ethereal solution was decanted and the residue was washed withi a small volume of ether and then triturated with a small volume of absolute ethanol to give 3.80g of 2,3-O-propionylidene-L-threitol 1,4-bis(methanesulfonate) as colorless crystals.

Yield: 83X 1.39 g of 2,3-0-propionylidene-L-threitol 1,4-bis (methanesulfonate) was reacted with sodium azide in the same manner as described in Preparative Example I to give 0.83 g of 4,5-bis(azidomethyl)-2-ethyl-1,3-dioxolane.

Yield: [a ID' 2 0 -1~27.540 (acetone) Synthesis of (4S,5S)-4,5-bis(aminomethl)-2-ethyl-1,3-dioxolarie 25 0.73 g of (4S,5S)-4,5-bis(azidomethyl-2-ethyl-l,3dioxolane was reduced in the same manner as described in Preparative Example 1 to give 0.51 g of (4S,5S)-4,5-bis(aminomethyl)-2-ethvl- 1, 3-dioxolane.

Yield: 93% Preparative Example 7: Synthesis of 4 R,5R)-4,5-bis(azidomethyl)-2,3-.dimethyl.

1, 3-dioxolane 5.04 g of 2, 3 -Q-isopropylidenie-D-threitoI 1,4-bis(methanesulfonate) was produced in the same procedure as described ii, J.

hed. Chem. 7, 14 (1964).

5.04 g of 2 ,3-0-isopropylidene-D-threitol 1, 4 -bis (methane-.

sulfonate) was reacted with sodium azide in the same manner as described in Preparative Example I to give 3.22 g of 4 ,5-bis(azidomethyl)-2,2-dimethyl-l,3.dioxolane as a light yellow oil.

Yield: 96% IR(neat): 2110 cm- 1 (N3) Synthesis of (4R,5R)-4,5-bis(aminomethyl)-2,2-dimethyl-1l 3 dioxolane 3.22 g of (4R, 5R)-4 ,5-bis(azjdometh 'l 2-dimethy 1-1,3dioxolane was reduced in the same manner as described in Preparative Example I to give 2.40 g of 4 methvl)-2,2-dimethyl-1,3-dioxolane as an oil.

Yield: 99% IR(neat): :3J70, 3306 cm- 1 (NI12) Preparative Example 8: Synthesis of 4 S,5S)-4,5-bis,-(azidonethyl)-2.2-dimethyl- 1 3 -dioxolane 3.30 g of 2 3 -Q-isopropylideie-L-lireitoI l,4-bis(metlianesulfonate) was produced by the same procedure as described ini J* Med. Chem., 7, 14 (1964).

25 3.30 g of 2 3 -0-isopropylideneL-.threito1 1,4-bis- (methanesulfonate) was reacted with sodium azide in the same manner as described in Preparative Example 1 to give 2.18 g of 4,-i...oety)2,-iety-,3-dioxolane.

Yield: 99% (21 Synthesis of (4S,5S)-4,5-bis(aminomethyl)22dimethyl-1 3 d ioxo lane 2.11 g of (4S,5S)-4,5-bis(azidomethyl).22dimeth,11, 3 dioxolane was reduced in the same manner as described in Preparative Example I to give 1.53 g of 4 S,5S)-4,5-bis(aminometh)2,2 dimethyl-l ,3-dioxolane.

Yield: 96X Preparative Examp~le 9: Synthesis of 4 R,5R)-4,5-bis(azidomethyl)-2-isopropyl- 1 ,3-dioxolane A mixture of D-tlrreitol l, 4 -bis(methanesulfonate)(H.00 g 14.4 mmol), isobutyraldehyde(U.14 g, 15.8 mmol), anhydrous copper (11) sulfate(3.44 g, 21.6 minol) and iethanesulfonic acid(2 drops) in anhydrous toluene(40 rnQ) was stirred at a room temperature for 16 hours under a nitrogen atmosphere. The reaction mixture truned to a solid mass and to it, ethyl acetate(50 WrQ) arnd anhlydrous potassium carbonate(O.3 a) were added. The reaction mixture r.~as stirred for an additonal 20 minutes, filtered, evaporated to drYnleSS under a reduced pressure, and purified by using flash column chromatography over silica gel with a mixture of ethyl acetatehexane(l:1, as the eluent to give 4.70 g of 2,3-0isobutylidene-D--threitol 1, 4 -bis(methanesulfonate) which was crystallized from absolute ethanol.

*~:Yield: 98% SM.P. 70. 0-70.5*C IR(KBr): 1360, 1332, 1182 cm- 1 (0-=S02) 'H NMR(CDCl3): J 0.95(d, J 6.8 Hz, 6 H, 2 CR3), 1.

82 (mn, 1 H, CH), 3.08(s, 6 H, 2 SOZCH3), 4.05-4.25 (mn, 2 H, 2 CH), 4 25 4 4 5(m, 4 H, 2 CH2), 4.86 J 4.6 Hz, 1 H, CH) 13C NMR(CDCl3): CT 16.50, 31.87, 37.75, 67.83, 67.91, 75.28, 75.66, 109.15 0% 0 Alternatively, 2 3 -0-isobutylidene-D-threitol 1,4-bis- *99: (methanesulfonate) may be prepared by the following method.

A mixture of diethyl D-tartrate(15.00 g, 72.7 inmol), isobutyraldehyde(26.23 g, 363.7 minol, 33.04 WQ), anhydrous copper (11) sulfate(23.22 g, 145.5 mmiol) and methanesulfonic drops) in anhydrous toluene(250 Wn was stirred at a room temperature for 16 hours under a nitrogen atmosphere. Anhydrous potassium carbonate(1.00 g) was added to the reaction mixture and stirred for an additional 20 minutes. The reaction mixture was filtered, evaporated to dryness and the oily residue was Vote.

S.

a.

*:so purified by using flash column chromatography over silica gel with a mixture of ether-hexane(1:4, v/v) as the eluent to give 15.95ag of diethyl 2 3 O0isobutylidene-D-tartrate as an oil.

Yield: 84X IR(neat): 1757 cm- 1

(C=O)

IH NHR(CDCI3): J~ 1.00(d, J 6.9 Hz, 3 H1, CH3), 1-01(d, J =6.9 Hz, 3 H, C113), 1.32(t, J 7.2 Hiz, 6 H, 2 GH3), 1.

9 6(m, 1 Ht, CIj(CH3)2), 4.27 J7.2 Hiz, 2 H1, C112), 4 2 8

J

7.2 Hzt, 2 H, CH2), 4.65(d, J =4.2 Hz, 1 H, OH), 4.73(d, J 4.2 Hz, 1 H, CH), 5.01(d, J 4.8 Hz, 1H, CH) 130 NMR(CDC1 3 6 13.99, 14.02, 16.50, 31.61, 61.66, 77.09, 77.21, 111.12, 169.02, 169.80 15.00g(57.6 mmol) of diethyl 2 3 -O-isobutylidene-Dtartrate was reduced in the same manner as described in Step I of Preparative Example 5 to give 6.89g of 2 3 -O-isobutylidene-Dthreitol as an oil.

Yield: 68% 20 IR(neat): 3382 cm- 1

(OH)

'H NNR(CDCI 3 (5 0.95(d, J 6.9 Hz, 6 H, 2 CH3), 1.

83 (m, 1 H, CH(CH3)z), 2.54(br s, 2 H, 2 OH), 3 68- 3 86 4 H, 2 CHz), 3.87-4.00(m, 2 H, 2 OH), 4.84(d, J4 4.5 Hz, 1 H, OH) 13C NMR(CDCl,): 6 16.62, 16.67, 32.12, 62.27, 62.33, 78.11, 78.89, 108.24 6.70g(38.0 mmol) of 2 3 O0isobutyldene-D-threitol was reacted with methanesulfonyl chloride in the same manner as described in Step I of Preparative Example 5 to give 11.13-g of 2 3 -0-isobutylidene-D-threitol1l,4 -bis(methanesulfonate).

Yield: 88% m. p. 70. 0-70. IR(KBr): 1360, 1332, 1182 cm- 1 (0-S02) 4.40 g of 2 3 -O-isobutylidene-D-threitol 1,4-bis(methanesulfonate) was reacted with sodium azide in the same manner as described in Preparative Example 1 to give 2.92 g of (4R,5R)-4,5bis(azidomethyl)-2-isopropyl-1,3-di ola as a light yellow oil.

Yield: 97X (a ID 20 +110.85' (acetone) IR(neat): 2103 cm-1 (N3) 'H NMR(CDCI3): 6 0.97(d, J 6.8 Hz, 6 H, 2 C113), 1.65-2.05 I H, CI), 3 2 0- 3 .60(m, 4 H, 2 CH2), 3.85- 4 .15(m, 2 11, 2 CH), 4.85(d, J 4.6 Hz, 1 I, CII) 3 C NNIR(CDCI): 16.51, 16.56, 32.00, 51.81, 51.91, 77.10, 77.90, 108.69 Synthesis of 4 R,5R)-4,5-bis(aminomethyl)-2-isopropyl.-1,3- 15 dioxolane 2.87 g of 4 R,5R)-4,5-bis(azidomethyl)-2-isopropyl-1, 3 dioxolane was reduced in the same manner as described in Preparative Example I to give 2.13 g of (4R,5R)-4,5-bis(ainoethyl)-2.

isopropyl-l,3-dioxolane as an oil.

Yield: 96% 20 JR(neat): 3369, 3301 cm- 1 (NH2) IH NbMR(CDCl3): 6 0.96(d, J 6.9 Hz, 6 H, 2 CH3), 1.33(s, 4 H, 2 NH), 1.75-1.

9 0(m, 1 H, CH), 2.75-2.98 4 H, 2 CH2), 3 .6 7 3 .7 7 2 H, 2 CH), 4.79 J 4.5 Hz, 1 H, CH) 3 C 14MR(CDC13): 16.65, 16.76, 32.06, 44.01, 44.25, 80.29, 80.91, 107.40 Preparative Example Synthesis of 4 S,5S) 4,5-bis(azidomethyl)-2-isopropyl- .1, 3 dioxolane 4.00 g of L-threitol 1ll-)is (metlanesulfonate) was reacted with isobutyraldehyde in the same manner as described in Preparative Example 9 to give 4.58 9 or 2 ,3--isobuty- ideiie--tlire itl 1,4-bis (methianesulfona e).

Yield: 96% 4.40 g of 2 3 -Q-isobutylidene-L-threitol 1, 4 -bis (methanesulfonate) was reacted with sodium azide in the same manner as described in Preparative Example I to give 2.90 g of (4S,5S)-4,5-.

bis(azidomethyl)-2-isopropy1q, 3-dioxolane.

Yield: 97% [a ]D 2 1 110.91* (acetone) Synthesis of 4 S, 5S)-4,5-bis(aminomethyl )-2-isopropyl1,3dioxolane 2.50 g of 4 S,5S)-4,5--bis(azidomethyl)-2-isopropyl1 3dioxolane was reduced in the same manner as described in Preparati -e Example 1 to give 1.85 g of (4S,5S)-4,5-bis(aminomethyl)-2isopropyl-1 ,3-dioxolane.

Yield: 96% Preparative Examnie 11: Synthesis of -(4,R,5R)-4,5-bi-s(azidomethy)-1,3-di-oxoarie- S*.-2-spiro-i -cyclopentane A mixture of D-threitol l,4-bis(niethannesulfonaLe)(10.OO g, 35. 9 mniol) cyclopentanone(6.-05 g, 7 1. 8 mmol, 6.4 mQ and methanesul fon ic acid(5 drops in benzene(l100 9 t) was ref luxed under a Dean-Stark continuous water separator for 16 hours. The reactionl mixture was cooled to a room temperature and to this clear, solution, anhydrous potassium carbonate(0.50 g) w;as added. The reaction mixture was stirred for an additional 20 minutes, filtered, evaporated under a reduced pressure, and the residue was crystallized from absolute ethanol to give 11.02 g of 2,3-0- :cyclopentylidene-D-threitol 1,4-bis(methanesulfonate) as white crystals.

Yield: 89% m. p. 89. 5-90.5*C IR(Nujol): 1357, 1179 cm- 1 (0-S02) 'H NNR(CDCl3): 6 1.50- 2 .00(m, 8 H, 4 CH2), 3.08(s, 6 H, 2 SO2CH3), 4 .10-4-25(m, 2 H, 2 CH), 4.25-4.50 4 H, 2 CH2) 1 3 C NMR(CDC3): 6 23. 35, 37. 15, 37. 66, 68.03, 75.10, 120.80 Alternatively, 2 3 -0-cyclopentylidene-D.-threitol 1,4bis(methanesulfonate) may prepared by the following method.

A mixture of diethyl D-tartrate(3.90 g, 18.9 mmol), cyclopentanone(6.53 g, 77.6 mmol, 6.86 MnQ) and methanesulfonic acid(3 drops) in benzene(60 MQ) was refluxed under a Dean-Stark continuous water separator for 16 hours. The reaction mixture was cooled to a room temperature and to this clear solution, anhydrous potassium carbonate(0.30 g) was added. The reaction mixture was stirred for an additional 20 minutes, filtered, evaporated to dryness, and the residue was purified by using flash column chromatography over silica gel with a mixture of ether-hexane(1:4, v/v) as the eluent to give 2.36 d of diethyl 2 ,3-Q-cyclopentylidene- D-tartrate as an oil.

15 Yield: 46% IR(neat): 1757 cm- 1 (C=0) IH NMR(CDCI3): 6' 1.32(t, J 7.2 Hz, 6 H, 2 CH3), 1.71(m, 4 H, cyclopentyl), 1.80- 2 .10(m, 4 H, cyclopentyl) 4.2 7 J 7. 2 Hz, 4 H1, 2 GH2 4. 72 2 Hf, 2 01i) 1 3 C NMN(CDCj3 65 14.04, 23.38, 36.55, 61.73, 76.99, 123.26, 169.53 6.12 g(22.5 mmol of diethyl 2,3-0-cyclopentylidene-Dtartrate was reduced by the same maiiner as described in Step I of Preparative Example 5 to give 2.57 g, of 2,3-0-cyclopentylidene-Dthreitol as white crystals.

Yield: 61X 53.0-53.5*C IR(KBr): 3283 cin 1

(OH)

'H NMR(CDCl3): J' 1.51-2.01(m, 8 H, cYclopentyl), 2.56(br s, 2 H, 2 OH), 3 6 1-3.87(m, 4 H, 2 CHz), 3.93 (br s, 2 H, 2 CH) 1 3 C NMNR(CDCI3): 6' 23.42, 37.36, 62.42, 78.52, 119.34 2.50g (l3.3mmol) of 2 3 -O-cyclopenty-lidene-D-threitol was reacted with methanesulfonyl chloride in the same manner as described in Step 1 of Preparative Example 5 to give 3.72g of 2,3- 0O-cyclopenty-lidene--D-threitol 1,4-bis(methanesulfonate).

Yield: 81% m.p. 89.5-90.5*C IR(Nujol): 1357, 1179 cm-' (0-S02) 5.00 g of 2,3-O-cy-clopentylidene--D-threitol 1,4-bis- (methanesulfonate) was reacted with sodium azide in the same manner as described in Preparative Example 1 to give 3.29 gof 4,5-bis(azidomethyl)-1,3-dioxolane-2-spiro-1'-cy-clopentane as a light yellow oil.

Yield: [a ]D 20 =+125.390 (acetone) IR(neat): 2101 cm- 1 (N3) 41 NMR(CDG13): J 1.50-2.05(m, 8 H, 4 CHz), 3.25-3.60(m,. 4 H1, 2 CHz), 3.89-4.09(m, 2 H, 2 CH), 3 C NhNR(CDC13): 65 23.25, 37.07, 51.73, 76.83, 120.15 Synthesis of (4R,5R)-4,5-bis(aminometl,)-1,3-dioxolanie?2 spiro-i '-cyclopentane 3.20 a of (.R,5R)-4,5-Ibis(azidomety1-)-1,3-dioxolaIie-2spiro-l '-cyclopentane was reduced in the same manner as descrbied in Preparative Example 1 to give 2.40 gof (411,5R)-4,5-bis(aminonethl1)-1,3-dioxolanie-2-spiro-I '-cyclopen Lane as an oil.

Yield: 96Z IR(neat): 3370, 3302 cm- 1 (NI-2) 1H- NIIR(CDGI3):6 1.36(s, 4a It, 2 INH2), 1.50-1.90(mn. 8 H, 4 CH2), 2.

77 -2.95(m, 4 H, 2 CH2), 3.68-3.78 3 C NR(CD3): (in, 2 H, 2 CH), 13C MR(CC13 6 23.23, 37.30, 44.13, 80.02, 118.45 Preparative Example 12: Synthesis of (4S,5 )-4,5-bis(azidomethyl)- 1, 3 -dioxolane-2-spiro-l1'cyclopentane 5.00 g of L-threitol 1,4-bis(methanesulfonate) was reacted with cyclopentanone in the same procedure as described in Preparative Example 11 to give 5.93 g of 2 3 -O-cyclopentylidene-L-threitol 1 ,4-bis(methanesulfonate).

Yield: 96% 90-91,C 5.73 g of 2,3-O-cyclopentylidene-L-threitol 1 ,4-bis(methanesulfo) was reacted with sodium azide in the same manner as described in Preparative Example 1 to give 3.85 g of (4S,5 )-4,5-bis(azidomethyl)-1,3-dioxoane2 spiro-i P-cyclopentane.

Yield: 97% -122.90* (acetone) *15 Synthesis of 4 S,5 -4,5-bis(aminomethyl)- 1,3-dioxolane-spo1 cyclopentane 2.86 g of (4,5 )-4,5-bis(azidomethyl)- 1,3-dioxolane-2-spiro-1'cyclopentane was reduced in the same manner as described in Preparative Example 20 1 to give 2.12 g of 4 $S )-4,5-bis(aminomethyl)-1,3-dioxolane-2-spiro-l-'- 0: cyclopentane.

Yield: Preparative Example 13: Synthesis of (4R,5R)-4,5bsazdmty),3dOlfl 2-spiro-i '-cyclohexane 4.00 g(14.4 mmol) of D-threitol 1,4-bis(methanesulfoflate) was reacted with cyclohexanone(2. 82 g, 28. 7 nimol, 2. 98 mQ in the same manner as described in Preparative Example 11 to give 4.73 g of 2,3-Q-cyclohexylidene-D-threitoI l,4-bis(methanesulfoflate) as white crystals.

Yield: 92X m.p. 95.5-96.5'C Alternatively, 2,--ylhxlieeDtrio 1,4-bis- (wethanesult'onate) mbay be prepared by the following method.

A mixture of diethyl D-tartrate(3.90 g, 18.9 rnmol), cyclohexanone(7-62 g,77.6 mniol, 8.04 Mn) and methanesulfonic acid(3 drops) in toluene(60 MQ) was refluxed under a Dean-Stark continuous water separator for 16 hours. The reaction mixture was cooled to a room teinperautre and to this clear solution, anhydrous potassium carbonate(0.30 g) was added. The reaction mixture was stirred for an additional 20 minutes, filtered, evaporated to dryness, and the residue was purified by using flash column chromatography. over silica gel with a mixture of ether-hexane(l:4, v/v) as the eluent to give 4.74 g of diethyl 2 3 -0-cyclohexylidne D-tartrate as an oil.

Yield: 88% IR(neat): 1757, 1735 cm-1

(C=Q)

'H NMR(CDCl3): 6 1.31(t, J 7.2 Hz, 6 H, 2 CH3), 1.37-1.47 2 H, cyclohexyl), 1.

57 -1.80(m, 8 H, cyclohexyl), 4 .27(q, J1 7.2 Hz, 4 H, 2 CH2), 4.77(s, 2 H, 2 CHI) 20 1 3 C NMR(CDCI3): J 13.98, 23.65, 24.78, 35.77, 61.63, 76.83, 114.40, 169.78 6.58 g(23.0 minol) of diethyl 2 3 -O-cyclohexylidene-D- *..*tartrate was reduced in the same manner as described in Step 1 of Preparative Example 5 to give 2.98 g of 2 3 -0-cyv;lohexylidene-Dthreitol as colorless crystals.

5 Yield: 64% m.p. 49.5-51.5'C IR(KBr): 3383 cm-1 (OH) 'H NMR(CDCI3): 6 1.

3 4 -1.49(mn, 2 H, cyclohexyl), l.63(br s, 8 H, cyclohexyl), 2.35(br s, 2 H, 2 OH),_ 3 .6 4 -3.86(m, 4 H, 2 CHz), 3.99(br s, 2 H, 2 CH) 2.70 g(13.3 inmol) of 2 3 -0-cyclohexylidene.D-threito1 was reacted with iethanesulfonyl chloride in the same manner as described in Step 1 of Preparative Example 5 to give 4.29 g of 2,3- O-cyclohexylidene-D-threitol l, 4 -bis(methanesulfonate).

Yield: 95.5-96.5*C 4.73 g of 2 3 cy*clohlexylidene-D-thireitol 1,4-bis- (methianesulfonate) was reacted with sodim azide ill the same manner as described in Preparative Example I to give 3.16 g of 4, i~ z d m t 1 i x l n p r 'c c oix n as a light yellow oil.

Yield: [af ]D 2 0 =+120.360 (acetone) IR(neat): 2100 cm- 1 (N3) IM NMR(CDC1 3 J 1.20-1.85(m, 10 H, 5 CH2), 3 2 1- 3 62 (mn, 4 H, 2 CH2), 3.95-4.15(m, 2 H, 2 CH), 1 3 C NMR(CDC13): 23.77, 24.93, 36.45, 51.70, 76.60, 110.99 !'Synthesis of (4R,5R)-4,5-bis(aminomethy1)-1,3-dioxolane-2spiro-i '-cyclohexane 3.10 g of (4R,5R)-4,5-bis(azidomethyl)-1,3-dioxoane-2spiro-l'-cyclohexane was reduced in the same manner as described in Preparative Example I to give 2.44 g of (4R, 5R) -4 5-bis (amino-.

methyl)-1,3-dioxolane-2--spiro-l'-cyclohexane as an oil.

Yield: 99% IR(neat): 3370, 3297 cm- 1 (NH2) 'H NNR(CDC1 3 6 1.37(s, 4 H, 2 NH2), 1.40-1.80(m, 10 H, CHz), 2.78-2.93(m, 4 H, 2 CH2), 3.70-3.80 (in, 2 H, 2 CH) 1 3 C NMR(CDC13): 6 23.71, 25.00, 36.74, 44.20, 79.55, 109.06 Preparative Example 14: Synthesis of (4S,5S)-4,5-bis(azidomethyl)-1,3-dioxolane- 2-spiro-i' -cyclohexane 5.00 g(18.0 mmol) of L-threitol 1,4-bis(raethanesulfonate) was reacted with cyclohexanone(3.53 g,35.9 minol, 3.72 me) ill the same manner as described in Preparative Example 11 to give 6.14 g of 2 3 -O-cyclohexylidene-L-threitol l, 4 -bis(methanesulfonate) as white crystals.

Yield: 5.94 g of 2 3 cyclohexylidene-L-threitoI 1,4-bis- (methanesulfonate) was reacted with sodium azide in the same manner as described in Preparative Example 1 to give 4.11 a of 4, S-bis(aziodomethyl 3 -dioxolane-2-spiro-I '-cyclohexane.

Yield: 98X [a ID 2 0 122.51* (acetone) Synthesis of 4 S,5S)-4,5-bis(aminomethyl)l13-.dioxolane-2 spiro-i '-cyclohexane 3.03 g of (4,S-,-i~zdmty)13dooae2 spiro-l'-cyclohexane was reduced in the same manner as described in Preparative Example 1 to give 2.35 g of (4S,5S)-4,5-bis(aminomethyl)-1 3 -dioxolane-2-spiro-l'-cyclohexane.

Yield: 98X Preparative Example Synthesis or (4R, 5R) 5-bis(azidometyl 2, 2-diethyl- 1, 3 dioxolane A mixture of D-threi tol I 4 -bis(methanesulfonate) 17 g 2150mmol), 3-etnn(.8g, 30.0 mmol, 3.17 rd and methanesulfonic acid(3 drops) in benzene(50 mU was refluxed under a Dean-Stark continuous water separator for 16 hours. The reaction :mixture was cooled to a room temperature and to this clear solution, anhydrous potassium carbonate(O.20 g) was added. The reaction mixture was stirred for an additional 20 minutes, filtered, evaporated under a reduced pressure, and the residue was crystallized from absolute ethanol to give 4.32 g of 2,3-0diethylmethylene-.D.threitol 1, 4 -bis(methanesulfonate) as white crystals.

Yield: 83X m.p. 53.5*C IR(KBr): 1351, 1170 cm-I (0-Sz) 11 NNR(CDC13): 6 0.92(t, J 7.3 Hz, 6 H, 2 CH3), 1.68 J 7.3 Hz, 4 H, 2 CH2), 3 .08(s, 6 H, 2 SO2CH3), 4 .0 8 -4.22(m, 2 H, 2 CH), 4.22- 4.44(m, 4 H, 2 CH2) 3 C NMR(CDCI 3 6 7.85, 30.17, 37.67, 67.85, 75.53, 114.85 4.26 g(12.3 mmol) of 2 3 -Q-diethylnethylene-D-threitol Sl,-bis(methanesulfonate) was reacted with sodium azide in the same manner as described in Example I to give 2.65 g of 4 ,5-bis(azidomethyl)-2,2-dieth-1-1,3-dioxolane as a light yellow oil.

Yield: (a IoO +105.89* (acetone) IR(neat): 2104 cm (N3) *H NMR(CDC13): 6 0.93(t, J 7.3 Hz, 6 H, 2 GH3), 1.70(q, J 7. 3 liz, 4 11, 2 CI12 3 2 7 3 63 4 11, 2 Clz), 3 89 -4.10(m, 2 H, 2 CH) C NR(CDC13): 6 7.91, 30.21, 51.75, 77.13, 114.16 20 Synthesis of (4R,5R)-4,5-bis(aminomethyl).2,2-diethyp 1 3 dioxolane 2.62 g(10.9 mmol) of (4R,5R)-4,5-bis(azidomethyl)-2? diethyl- 1,3-dioxolane was reduced in the same manner as described in Preparative Example I to give 2.05 g of 4 R,5R)-4,5-bis(aminomethyl)-2,2-diethyl-1,3-dioxolane as a colorless oil.

Yield: 100% IR(neat): 3374, 3299 cm- 1 (NH2) 'H NMR(CDC3): 6 0.91(t, J 7.3 Hz, 6 H, 2 CH3), 1.39(s, 4 H, 2 NH2), 1.

6 5(q, J 7.3 Hz, 4 H, 2 CHz), 2 6 8 3 .04(m, 4 H, 2 0Hz), 3.60- 3.87(m, 2 H, 2 CH) 1 3 C NR(CDC13): 6 8.01, 30.56, 44.24, 80.50, 112.41 Preparative Example 16: Synthesis of (4R, 5R) 5-bis (azidomethyl) -4-ethyl-2methyl-i, 3 -dioxolane A mixture of D-threitol lt 4 -bis(methanesulfonate)(3.50 g 12.6 mmol), 2 -butanone(70 MP), anhydrous copper(i1) sulfate(3.01 g, 18.9 mmol) and concentrated sulfuric acid(0.1 inQ) was stirred at room temperature for 16 hours under a ni trogeni atmosphere. The reaction mixture was filtered and tile filtrate was neutralized with 28% of ammonium hydroxide solution. The f il1tered soIltionl was io evaporated to dryness and crystallized from absolute ethanol to give 3.69 g of 2 3 -0-(1-methylpropylidene)D..threitol 1,4--bis (methanesulfonate) as white crystals.

Yield: 98X m-p. 71.5-72.5C IR(KBr): 1352, 1332, 1182 cm- 1 (0-SO?) to 'H NMR(CDCl 3 CT 0.94(t, I 7.3 Hz, 3 H, C-H3), 1.38(s, 3 H, 1.70(q, !I 7.3 Hz, 2 H, H) o. 3 .08(s, 6 H, 2 SO2CH3), 4 .0 2 4 .27(mn, 2 H, 2 CH), 4 3 1-4.45(mn, 4 H, 2 CH2) '3C NMR(CDCI 3 &5 8.01, 24.59, 32.69, 37.70, 67.74, 67.97, 75.02, 75.60, 112.90 3.50 g901.7 mmol) of 2 3 -0-(l-methylpropylidee)..threitol l, 4 -bis(methanesulfonate)warecdwihsiu ze in the same manner as described in Preparative Example 1 to give 2.35 g of (4,R-,-i~zdmtyl--ty--ehl13 dioxolane as a light yellow oil.

too. Yield: 88% (a ID 2 0 +128.24@ (acetone) IR(neat): 2105 cm- 1 (N'3) 11H NMR(CDC1 3 (50.96(t, J=7.3 Hz, 3 H, CH3), 1.

4 1(s, 3 H, CH3), 1.

7 3 J 7.3 Hz, 2 H, CH-2), 3 2 3 3 .65(m, 4 H, 2 CH2), 3 8 8 -4-18(m, 2 H, 2 CH-) 13C NMR(CDCl,): (5 8.04, 24.53, 32.82, 51.61, 51.70, 76.65, 77.32, 112.28 Synthesis of (4R,5R)-4,5-bis(aminomethyl)-2-ethi-2-meth..I- 1, 3-dioxolane 2.70 g(l1.9 mmol) of (4R,5R)-4,5-bis(azidonethyl)-2ethyl1-2-methyl-l,3-dioxolane was reduced in the same manner as described in Preparative Example 1 to give 2.08 g of (4R,5R)-4,§5.

bis(aminomethyl)-2-ethyl-2-methyl-1,3-dioxolane as an oil.

Yield: IR(neat): 3373, 3319 cmr 1 (NH2) 'H NMR(CDCI3): 03 0.94(t, J 7.4 Hz, 3 H, CH3), 1-35(br s, 7 H, CH3 and 2 NH2), 1.68(q, J 7.4 Hz, 2 H, CHz), 2 7 1- 3 .03(m, 4 H, 2 CH2), 3.63- 3.93(m, 2 H, 2 CH) 1 3 C NNR(CDC13): c35 8.10, 25.01, 33.01, 43.99, 44.24, 79.84, 80.55, 110.49 Preparative Example 17: Synthesis of- 4 R,5R)-4,5-bis(azidomethyl)-2-propy>-13dioxolane A mixture of D-threitol l, 4 -his(methianesulfonate)(3.50 g 12.6 mmol), n-butvraldehyde(I.00 g, 13.8 mmol, 1.5-12, nivru *s.copper( II sulfate(3. 01 g,18. 9 mmol and methanesulfonic acid drops) in anhydrous toluene(35 mC was stirred at a room atemperature for 16 hours under a nitrogren atmosphere. The reactionl mixture was added with anhiydrous potassium carboiiate(0.30 and stirred for an addi tonal 20 minutes. The reaction mixt'ure was filtered, evaporated to dryness and crystallized from absolute ethanol to give 4.10 g of 2 3 -O-butylidene-D-threitol 1,4-bis (methanesulfonate) as white crystals.

Yield: 98X m.p. :59.0-59.5'C IR(KBr): 1360, 1332, 1782 cm- 1 (0-S02) 'H NhR(CDCI 3 (3 0.95(t, J =7.4 Hz, 3 H, CH3), 1-45(m, 2 H, CH2), 1.66(m, 2 H, CH2), 3.08(s, 6 H, 2 SOZCH3), 4 1 0- 4 2 7(m, 2 H, 2 CH), 4.27- 4-50(m, 4 H, 2 CH2), 5.10(t, J 4.6 Hz, 1 H, CH) 3 C NMR(CDC1 3 6 13.88, 17.02, 35.83, 37.74, 67.80, 68.06, 75.06, 75.69, 105.49 4.01 g(12.1 mmol) of 2 3 -0-butylidene-D-threitol 1,4-bis- (methanesulfonate) was reacted with sodium azide in the same manner as described in Preparative Example I to give 2.45 g of 4,5-bis(azidomethyl)-2-propyl-1,3-dioxola as a light yellow oil.

Yield: (a )D 2 o +119.968 (acetone) IR(neat): 2104 cm- 1 (N3) 'H NMR(CDC13): d 0.96(t, j= 7.4 Hz, 3 H, CH3), 1.46(m, 2 H, CHz), 1.6 7 2H, CHz), 3 3 0-3.60(m, 4 H, 2 GHz), 4.01(br s, 2 H, 2 CH), 5.10 J 4.5 Hz, 1 H, CH) 3 C NMR(CDC 3 6 13.92, 17.11, 36.09, 51.87, 51.96, 76.89, 77.90, 105.02 Synthesis of 4 R,5R)-4,5-bis(aminomethyl)-2-prop 3 1lJ dioxolane 2.37 g(10.5 mnol) of 4 R,5R)-4,5-bis(azidomethyl)-2propyl-1,3-dioxolane was reduced in the same manner as described in Preparative Example 1 to give 1.81 g of 4 R,5R)-4,5-bis(aminomethyl)-2-propyl-1,3-dioxolane as an oil.

Yield: 99% IR(neat): 3368, 3297 cm- 1 (NH2) H NMR(CDC13): S 0.95(t, J 7.2 Hz, 3 H, CH3), 1.45(m, 2 H, CHz), 1.63(m, 2 H, CHz), l.68(s, 4 H, 2 NH2), 2 7 0 -3.05(m, 4 H, 2 CH2), 3.

7 5(br s, 2 H, 2 CH), 5.03(t, J 4.2 Hz, 1 H, CH) 13 C NMR(CDC13): (5 14.01, 17.23, 36.27, 43.94, 44.24, 80.f5, 81.01, 103.71 Preparative Example 18: Synthesis of 4 R,5R)-4-,-5-bis(azidomethyl) -2-isobutvyll,3-dioxoane 3.50 g(12.6 mmol) of D-threitol l, 4 -bis(methanesulfonate) was reacted with isovaleraldehyde(1 19 g, 13.8 mmol, 1.48 mQ) in the same manner as described in Preparative Example 17 to give 4.18 g of 2 3 -0-isopentylidene-.D-threitol1l, 4 -bis(methariesulfonate) as white crystals.

Yield: 96% m. p. :85.5-86*C IR(1KBr): 1356, 1333, 1181 cMr 1 (0-SO?) 'H NMR(CDC.1 3 6 0.-95 J 6. 6 Hiz, 6 11, 2 CH3) 1.58 (dd, J 4.9 Hz, 6.8 Hz, 2 1H, CH2), I.79(m, 1 11, CIO), 3 .09(s, 6 H1, 2 SOZCH3), 4.18 (br s, 2 11, 2 CH), 4 .2 7 -4.50(m, 4 it, 2 cwz), 5.13(t, J 4.9 Hz, I H, C11) 1 3 C NMR(CDCI 3 6 22.82, 22.88, 24.38, 37.80, 42.67, 67.75, 68.05, 74.98, 75.73, 104.91 4.08 g of 2 3 -0-isopentylidene-D-threitol 1,4-bjs- (methanesulfonate) was reacted with sodium azide in the same manner as described in Preparative Example 1 to give 2.78 g of 4,*i~zdmty)2iouy-,-ixln as light Yellow, oil.

Yield: 98% 20 (a ]D 2 0 +118.440 (acetone) IR(neat): 2103 cm- 1 (N3) IH NMR(CDC13): 6 0.96(d, J 6.6 Hz, 6 H, 2 CH3), 1.59(dd, J 5.1 Hz, J 6.6 Hz, 2 H4, CH2), 1.

8 3(m, 1 H, CH), 3 30 3 .60(m, 4 H, 2 CR2), 4.01 a 25 (br s, 2 H, 2 CH), 5.13(t, J=5.1 Hz, 1 H, CH) 1 3 C NMR(CDCl 3 6T 22.81, 22.89, 24.44, 42.89, 51.88, 51.96, 76.77, 77.85, 104.38 30(2) Synthesis of 4 R,5R)-4,5-bis(aminomethl).2...isobutl1 3 dioxolane 2.71 g90l.3 mmol) of 4 R,5R)-4,5-bis(azidomethyl).2isobutyl-1,3-dioxolane was reduced in the same manner as described in Preparative Example 1 to give 2.12 a. of 4 R,5R)-.4,5-bis(aminomethyl)-2-isobutyl-.1,3..dioxolane as an oil.

Yield: 100% IR(neat): 3370, 3295 cm- 1

(NH?)

t4HR(CDC1 3 jY 0-95(d, J =6.6 liz, 6 11, 2 Cf-b), 1.55(dd, J =4.9 Hiz, J =6.8 Hz, 2 11, CH2), 1.

8 1(, 1 H, CIO), 2-03(s, 4 11, 2 N112), 2.73-~2.93 (mn, 4 If, 2 N112 3. 73(br s, 2 H, 2 C11), 5.06(t, I 4.9 Hiz, 1 II, Cli)

NNR(CDC

3 6 22.98, 24.46, 43.06, 43.78, 44.13, 79.88, 80-89, 103.07 Preparative Example 19: Synthesis of 4 RSBg)-4,5-bis(azidomethyl)-2.tert..butyl-l, 3 -dioxolane 3.50 g (12.6 mmol) of D-threitol l, 4 -bis(methanesulfonate) was reacted with trimethylacetaldehyde (1.19 g, 13.8 mmol, 1.50 ml) in the same manmer as described in Preparative Example 17 to give 2.08 g of 2,3--Oneopentylidene-D..thrcito l, 4 -bis(methanesulfonate) as white crystals.

Yield: 48% 100.0'C IR9) 138 1331..,, 1181 cm'(0-SO 2 999 1H NMR (CDC13): 6 0.92 9 H, 3 CU 3 3.07 3 H, SO 2

CH

3 3.08 3 H, S0C3,4.10-4.24 (,2H, V 2C1{), 4.24-4.50 (in, 4H, 2 CH2), 4.74 (s, 9 *11H,

CH)

13 C NMR(CDC13): 8 24.06, 34.19, 37.74, 37.79, 67.81, 67.91, 9 9 75.49, 75.67, 110.98 25 1.98 g of 2,3-0-neopentyIi 1,4bi~ehnsloae was reacted with sodium azide in the same manner as described in Preparative Example 1 to give 1.36 g of (4R,5R)-4,5bis(azidomethyl).2..ter.t..butyl...,3....oj 0 01 e as a light yellow oil.

Yield: 99% [a ID 20 +104.69* (acetone) IR(neat): 2103 cm- 1 (N3) 'H NMR(CDCI 3 6T 0.94(s, 9 H, 3 CH3), 3 3 2 -3.49(m, 4 H, 2 Cflz), 3 9 2-4-04(m, 2 H, 2 CHi), 4 7 4(s, 1 H, CHI) 11C NMR(CDCI3): d 24.05, 34.16, 51.73, 51.88, 77.31, 77.91, 110.53 Synthesis of (4R,5R)-4 Sbis(aiinomethyl)2tert-butyl-1, 3dioxolane 1.29 g(5.4 mwol) of 4 R,5R)-4,5-bis(azidomethyl) 2 tet butyl-~1,3-dioxolane was reduced in the same manner as described in Preparative Example 1 to give 1.00 g of (4R,5R)-4,5-bis(aminomethyl)-2-tert-.butyl1, 3 -dioxolane as an oil.

Yield: 99X IR(neat): 3366, 3295 cm- 1 (NH2) 'H N.MR(CDC1 3 6 0.

9 2(s, 9 H, 3 CH3), 1.49(s, 4 H, 2 NH2), 2.70-3.00(m, 4 H, 2 Cli?), 3 66 -3.80(m, 2 H, 2 CH), 4-66(s, I H, CH) 1 3 C NMR(CDCl 3 6 24.31, 34.33, 44.03, 44.18, 80.43, 80.96, 109.50 of a 29 THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS: 1. A 4 ,5-bis(aminomethyl)-l,3-dioxolane compound of the formula RI 0 NH2 XNH R2 0 -NH2 wherein R, and R, are the same or different and are selected from the group consisting of a hydrogen atom and a C, C 4 alkyl group, or together form a cycloalkane group with the carbon atom attached therto with the proviso that R and R, are not simultaneously methyl; and wherein the absolute configurations at the respective chiral centres in the 4 ,5-bis(aminomethyl)-l,3-dioxolane moiety are or 2. A process for preparing a 4 ,5-bis(aminomethyl)-1,3-dioxolane :*.**compound of the formula which comprises: reducing a 4 ,5-bis(azidomethyl)-1,3-dioxolane compound of the formula with hydrogen in the presence of a palladium-chargoal or platinum (II) oxide in an alcoholic medium under a pressure between 0 and 70 psi and at a S 20 temperature between 0 and 50°C for from 30 minutes to 1 day, RI NH2 R 1 X R2 0 NH2 5

R

I 0 N3 SR 0 -N3 wherein,

R

1

R

2 and the absolute configurations are the same as defined in claim 1,

Claims (2)

1. 3. A 4
2. 5-bis(azidomethyl)-1,3-dioxolane compound of the formula: RI 0-N3 R 2 0 N ::wherein R, and the absolute configurations are the same as defined in claim 1. S* 4. A 4 ,5-bis(aminomethyl or azidomethyl)-1,3- dioxolane compound as defined in claim 1 or claim 3 and S: 25 substantially as herein specifically described in the Preparative Examples. A process for preparing a 4 or azidomethyl)-1,3-dioxolane compound as defined in claim 1 or claim 3 and substantially as herein described in any one fo the Preparative Examples. DATED this 21st day December 1998 SUNKYONG INDUSTRIES, LTD. By their Patent Attorneys CULLEN CO. 4 31 ABSTRACT Novel intermediates useful for the preparation of platinum (II) complexes having anti-tumor activity. The intermediates comprises 4 ,5-bis(aminomethyl or azidomethyl)-1,3-dioxolanes of the formula R I O NHz (or N 3 R 0 NH2 (or N 3 wherein R, and R 2 are the same or different and are selected from the group consisting of a hydrogen atom and a C, C 4 alkyl group, or together form a cycloalkane group with the carbon atom attached thereto, with the proviso that R, S. and R, are not simultaneously methyl; and wherein the absolute configurations at the respective chiral centres in the 4 ,5-bis(aminomethyl)-1,3-dioxolane moiety are or *oo