JPS6045590A - C-1 thiophosphinic acid ester derivative of saccharide and its preparation - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [R is H, CH3, CH2OH, OH, OCH2 Ph (Ph is phenyl), OCOCH3, OCH3, CH2OCH3, CH2OCPh3, CH2OCH2Ph, CH2 OCOCH3, NHCOCH3, >C(CH3)2 or >CHPh; R1 and R2 are (substituted) alkyl or aryl]. EXAMPLE:2,3,4,6-Tetrabenzyl-alpha-D-glucopyranose dimethylthiophosphinic acid ester. USE:Synthetic intermediate of glycoside compound useful in the fields of pharmaceuticals and agricultural chemicals, as antibiotic substance, carcinostatic agent, etc. PREPARATION:A sugar having hemiacetal bond at C-1 position is made to react with a strong base such as n-butyl lithium, thallium ethoxide, etc., and then with the phosphonothioyl halide of formula II (X is halogen) preferably dimethylphosphonothioyl halide).

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a thiophosphinic acid ester derivative at the C-1 position of sugar and a method for producing the same.

Glycoside compounds are widely distributed in nature, and are attracting attention because they are used as physiologically active substances, such as antibiotics and anticancer agents, in medicine, and other drugs. On the other hand, as a method for its synthesis, a method using sugar or sugar ester as an intermediate is known, but this method cannot be used industrially due to the lack of stability of these intermediates and the use of harsh reaction conditions. is still unknown.

Among the conventionally known methods using sugar esters as intermediates, B, Helferich and E, Shimft
g-Rule brecht method (Cham, Ba
r, vol. 66, 378 Jj (1933, Germany)] is known as a commonly used method.

In this method, sugar acetate is reacted with phenol, but it must be heated and melted under highly dehydrated conditions.
Industrialization is difficult.

As a result of intensive research in view of the above circumstances, the present inventors came to invent a sugar ester that provides a glycoside compound under mild conditions.

That is, the gist of the present invention is a thiophosphinic acid ester derivative at the C-1 position of sugar and a method for producing the same.

The present invention will be explained in detail below.

Well-known sugars can be used as raw materials for the monosaccharide C-1-position thiophosphinic acid ester derivative of the present invention.

It is necessary that the C-1 position of these sugars has a hemiacetal bond. The cyclic hemiacetal may be a 5-membered ring or a 6-membered ring. Usually aldoses are used, but ketoses can also be used. Specifically, these sugars include tetraose, such as erythrose and threose, and ribose.

Pentose, glu' such as arabinose and xylose: 2
-su, i rough)-su, mannose, allose.

Use of partially deoxylated sugars such as hexoses such as talose or deoxyribose, amino sugars such as N-acetylgusacosamine, and even oligosaccharides in which these sugars are ether-linked to each other. I can do it. These sugars are 0.

Both the L-form and mixtures thereof can be used.

It goes without saying that these sugars can be used with all the hydroxyl groups other than the C-1 position protected, but those having free hydroxyl groups protected to the minimum extent necessary for solubility etc. may also be used.

As the hydroxyl retaining group, conventionally known ones can be used. Specifically, methods of protection with acyl groups such as acetyl, trifluoroacetyl, trichloroacetyl, benzoyl, P-nitrobenzoyl, etc., methods of acetalization with acetaldehyde, acetone, etc., and hydrocarbon groups such as methyl, benzyl, triphenylmethyl, etc. For example, the method of etherification can be mentioned.

As the halogenated phosphinothioyl used as another raw material in the method of the present invention, well-known ones can be used. That is, various halides such as dimethylphosphinothioyl, diethylphosphinothioyl, methylphenylphosphinothioyl, and diphenylphosphinothioyl can be used.

The halogen may be any of fluorine, chlorine, bromine, and iodine, but chloride and bromide are usually used.

As the strong base, well-known ones can be used. That is, alkali metals such as sodium metal, lithium metal, and potassium metal, metal alcoholades such as sodium methoxide and thallium ethoxide, alkali metal hydrides such as sodium hydride, alkyl metals such as n-butyllithium, phenyllithium, etc. Aryl metals or l, 8-
These include strongly basic amines such as diazabicyclo-(5,4,0)-undecene-7.

Although it is possible to use the halogenated phosphinothioyl and the strong base in large excess relative to the sugar, the amount is usually 1 to 2 molar equivalents.

There are no particular restrictions on the solvent. i.e. benzene,
Examples include toluene, chloroform, dichloromethane, ethyl acetate, titrahydrofuran, dimethylformamide, acetonitrile, nitromethane and the like.

The reaction temperature is not particularly limited from -60°C to the boiling point of the solvent.

Thiophosphinic acid esters at the C-1 position of sugars exist in α-form and β-form, and although it is possible to separate these from a mixture, it is possible to select one by changing the solvent, base 1 reactivity, etc. It is also possible to manufacture it with high efficiency.

EXAMPLES The present invention will be described in more detail with reference to Examples below, but the present invention is not limited in any way by the Examples unless the gist of the invention is exceeded.

Example 1 2.70 f (5 mmol) of 2.3,4,6-titrabenzyl-D-glucobylanose was dissolved in tetrahydro7 run (20 mg) and cooled to -30°C under a nitrogen atmosphere. Add 3.4 ml (5.4 mmol) of 1.6 Mn-butyllithium hexane solution to this,
After 0 minutes dimethylphosphinothioyl chloride 0.69F (5
,,4 mml). The reaction solution was stirred at -30°C for 3 hours and then returned to room temperature. Ether and water were added to this to separate the layers, and the ether layer was washed with water, dried, and concentrated under reduced pressure to yield 3.71
An oily substance of f is obtained. This was subjected to silica gel column chromatography (2, sx4zm) using dichloromethane as the eluent.
After purification, 2,3,4,6-titrapendyl-D-glucobylanose dimethylthiophosphinic acid ester was obtained as white crystals of 2.41F (76 mol). The ratio of α and β forms was 98:2. Decantation with n-hexane gives 2,3,'4,6-
Titrabenzyl-α-D-glucopyranose dimethylthiophosphinoic acid ester was obtained. Melting point 62-64℃
NMRδ (■C14, ppm) 1.86 (d,
6 H, P-CH,.

J=13H2) 6.18 (d, d, IH, H-1.

Example 2 2.38 t (4.4 mm 1.) of 2.3,4.6-titrabenzyl-D-glucobylanose was dissolved in 20 tIt of tetrahydrofuran, and 1.6 M n-butyllithium was dissolved at 0°C. /n-hexane solution 2.75 tnl (4
, 8'm) and dimethylphosphinothioyl chloride 0.
The same procedure as in Example 1 was conducted using 62 t (4.8 mmot). Purification with silica gel column chromatography (2,5xao6n) using dichloromethane as eluent yields
2,3,4.6-titrabenzyl-D-glucobylanose dimethylthiophosphinic acid ester as an oily substance at 2.78? (99 mol%) was obtained. α from NMR
The ratio of isomers to β-bodies was so:so.

Example 3 1.08 f (2 mml) of 2.3,4.6-titrabenzyl-D-glucobylanose (2 mml>'e) was dissolved in tetrahydrone 10-, and 1.6 Mn-butyllithium/
A reaction was carried out in the same manner as in Example 1 under refluxing tetrahydrofuran using n-hexane solution 138g (2.2mmt) and dimethylphosphinothioyl chloride 0.2839g (2.2mt). When purified in the same manner as in Example 1, 2
, 3,4.6-titrabenzyl-D-glucobylanose dimethylthiophosphinic acid ester as an oily substance.
．． 14f (90 mol q6) was obtained. The ratio of α and β forms was 40:60.

Example 4 1.08 t (2 mmot) of 2.3,4.6-chitrabenzyl-D-glucobylanose was added to 1 otn of benzene.
1. and tetrahydrone run 1 Otnt. To this was added 0.15 td (2.1 mrmL) of thallium ethoxide while bubbling with nitrogen, and the mixture was stirred at room temperature for 15 minutes. The solvent was distilled off under reduced pressure, and after drying, benzene 1
0.28 t (2,' 2 mmol, ) of dimethylphosphinothioyl chloride.
was added and reacted for 4 hours. Thereafter, the product was purified in the same manner as in Example 1 to obtain 0.38 F (30 mol) of 2,3,4,6-titrapendyl-D-glucobylanose dimethylthiophosphinic acid ester as white crystals.

The ratio of α and β forms determined by NMR was 9:91, n-
2°3.4.6 by decantation with hexane
-Titrabenzyl-β-D-glucopyrano-sdimethylthiophosphinic acid ester was obtained. Melting point 76-77
°C NMR (CDC4, ppm) 1.85 (d, d
, 6H,P-CHI.

J=13Hz, 8Hz) 5.37 (d, d, IH, H-1.

J=13 Hz, 7 Hz) Example 5゜2.3,4.6-thitrapendyl-D-galactopyranose 65.91 lv (0.12 mmt), 20%
n-Butyllithium/n-hexane solution 63.1 μt (
The same procedure as in Example 1 was carried out using 16.7 mg (0.13 mmol) of dimethylphosphinothioyl chloride and 1 tnt of tetrahydrofuran.

The crude product extracted with ether was purified by silica gel thin layer chromatography (zoxzocrn) to give 54.2
mg (over 72 mol) of 2,3,4,6-chitrabenzyl-D-galactopyranose dimethylthiophosphinic acid ester was obtained as an oil.

NMR (CDCIB, ppm) 1.63-2,
l l (m, 6) I, P-CHJ7.36 (S,
20H, Ph) Example 6 2.3,4.6-thitrapendyl-D-mannopyranose 108.1119 (0,2 mmot), 20
% n-butyllithium/n-hexane solution 103.1
pt (0.22 mmot) r Dimethylphosphinothioyl chloride 28.3 kg (0.22 mmot) *The same procedure as in Example 1 was carried out using tetrahydrofuran l-. When purified in the same manner as in Example 5, 94.911v (7
5 molti) was obtained.

NMR (CDC4, ppm) 1.82 (dd, 6H
, P-CH3.

J=13Hz, 8Hz) 6.11 (dd, IH, H-1.

J=13Hz, 2Hz) Example 7゜2.3.4-) Ribenzyl-D-arabinopyranose 6
0. 'ly (0,14mmo1.), 20%
n-Butyllithium/n-hexane solution 72.8 J
The same procedure as in Example 6 was carried out using 19.3 mg (0.15 mmt) of dimethylphosphinothioyl chloride and 1IRt'i of tetrahydrofuran. 2,3.4-) Lipendyl-D-arabinopyranose dimethylthiophosphinic acid ester as an oily substance 4
4.2 sy (at morch) was obtained.

NMR (CDC4, ppm) 1.49-2.11 (
m, 6H, P -CHl) 7.38 (8, 15H, P
h) Example 8゜2-acetamido-3,4,6-)lipendyl-D-glucobylanose 84.01119 (0,17 mmoL
)20% n-butyllithium/n-hexane solution 1
214 μt (0.26 mmoL), dimethylphosphinothioyl chloride 33.4119 (0.26 mmoL)
t), Example 6 using 31 nt of tetrahydrofuran
I went in the same way. 2-acetamido-3,4,6-)
Ribenzyl-D-glucopyranose dimethylthiophosphinic acid ester was obtained as an oily substance in an amount of 33.9η (34 mol).

NMR (CDC4, ppm) 1.45-2.10 (
m, 6H, P-CHa)1.86 (S, 3)I
, CH, Co) Example 9 1.34 t (3,1
7mmot) was dissolved in tetrahydrofuran 2o-,
1.6M n-butyllithium/n-hexane solution 2.1
3 ml (3,41 vnmol, ), dimethylphosphinothiol chloride kO,43f (3,41 mmol)
The same procedure as in Example 1 was carried out using L). Dichloromethane and water were added to the reaction solution to separate the layers, and the dichloromethane layer was washed with water, dried, and concentrated under reduced pressure to obtain 1.33 t of amorphous solid. When this was purified by silica gel column chromatography (2,5x4acIn) using ethyl acetate as the eluent, 6
- Dolythyru D-glucopyranose dimethylthiophosphinic acid ester as white crystals 0.47? (28 mol) was obtained. Melting point 114-117℃, NMRa (p
pm) 1.40-2.06 (m, 6H, P-CH
l) 6.80-7.66 (m, 15H, Ph) Example 10 2.3,4.5-tetrabenzyl-D-curcopyranose 108.1 q (0.2 mmol), 20%
n-butyllithium/n-hexane solution 103.1
The same procedure as in Example 6 was carried out using μt (0.22 mmol), 55.6 kg (0.22 mmol) of diphenylphosphinothioyl chloride, and tetrahydro7ran 1-. 2
81.31 (55 mol) of 3.4.6-titrabenzyl-α-D-/rucobylanose diphenylthiophosphinic acid ester were obtained as an oily substance.

NMR (CDCta, ppm) 6.38 (dd
, IH, H-1.

J=13Hz, 3Hz) 6.98-8.26 (m, 30H, Ph) Example 1
1 3.5.6-) Lipenzyl-D-glucofuranose 11
4.6 q (0.25 mmol), 20'ir
n-Butyllithium/n-hexane solution 131. Opt
(0.27 mmot) + 35.2 mg of dimethylphosphinothioyl chloride (0.27 mmoL) *The same procedure as in Example 6 was carried out using tetrahydrone ltd'i. 57,911 v (42 mol %) of 3,5.6-)lipendyl-α-D-glucofuranose dimethylthiophosphinic acid ester was obtained as an oily substance.

NMR (CDC4, ppm) 1.86 (d, 6
H, P-CH3.

J=13Hz) 6.62 (dd, 11.H-1゜J=13Hz, 4Hz) Example 12 Diphenylphosphinothioyl chloride 68.24 (0,2
The same procedure as in Example 11 was carried out using 7m (capital) L). 80q (48
Morti) obtained.

NMR (CDC4, ppm) 6.80 (dd,
IH, H-1.

J=13Hz, 4Hz) 6.95-8.32 (m, 25H, Ph) Reference example 1゜2.3,4.6-titrabenzyl-D-gluco'pyranose dimethylthiophosphinic acid ester 126.5kg (
0.2 m t) was dissolved in tetrahydrofuran (2 m), and 28.9 rq (0.2 mm 1.) of cyclohexyltrimethylsilyl ether and 41.5 rq (0.2 m t) of silver perchloride were dissolved in tetrahydrofuran (2 m). The mixture was added and stirred at room temperature overnight. An aqueous solution of IJium sulfide (556 sulfide) was added to the reaction solution, filtered, and extracted with ether. The organic layer was washed with water, dried, and concentrated under reduced pressure to obtain an oily substance. This was processed using silica gel thin layer chromatography (developing agent: n-hexane:ether-4:l) to obtain ynt1! i! As a result, cyclohexyl 2. s, 4.6-tetohy benzyl-D-glucopyranoside is 61.6tIIg (5Q mol%) Bn Bn: pendyl group (rinidichlorohexyl THF: tetrahydrofuran reference example 2゜2.3,4.6-thitrapendyl-α-D -G4A%1
86.5η (0.2 mmol) of β-cholestanyl trimethylsilyl ether was placed in a reaction vessel, and a solution of 41.5~(0.2 mmol) of silver perchlorate in tetrahydrofuran (2 mmol) was added thereto, and the mixture was stirred at room temperature. The mixture was stirred overnight.Then, treatment was carried out in the same manner as in Reference Example 1, yielding 109.3η (60 mol%) of β-cholestanyl 2.s, 4.6-teto-5-Zendi-β-D-glucopyranoside as white crystals. Melting point: 93.5°C.

Ca 7', % + 2o, 2c' (c 1.04, c
acz,)t*,/-:l:11/Stannyl 2,3
, 4,6-titrapendyl-α-D-glucopyranoside was obtained as white crystals at 35.81+9 (20 molar ratio). Melting point J 17.5-119°C.

α [Bitter]: +65.0' (C1,06, CHC4)%
Patent applicant Noguchi Institute procedural amendment (voluntary) September 260, 1980 Director General of the Patent Office Manabu Shiga λExemption 1, Indication of the case 1981 Relationship to Patent Application No. 139058 Case Patent applicant residence Tokoro Name 5, Contents of the date correction of the amendment order, 813 Particulars, page 25, line 5 from the top r ・109.3-
/(6omol%)-J to r・35.8'/(20mol%
)…”.

8th and 9th lines from the top of page 25 of the specification “... close 35
．． 8 grams (20 moles)..." to 109
．． Correct to 3”/(60 molti)...”.

that's all

Claims (1)

[Claims] 1. General formula CI) (wherein R is -H, -OH,, -CH, OHI -OHl
-OCH*Ph, -0COCHa, -0CH
I, -CHloC)fa. -CH,0CPh, , -C)(,OCH,Ph,
~CH, OCOCa. -NHCOC Horse >C(CHn)*, ) Caph (7t and ph indicates a phenyl group). - represents an unsubstituted or substituted alkyl group or aryl group. ) A thiophosphinic acid ester derivative at the C-1 position of a sugar. 2. The thiophosphinic acid ester derivative at the C-1 position of a sugar according to claim 1, wherein in the general formula CI), R8 and avian are methyl groups. 3. C- of the sugar according to claim 1, wherein in the general formula CI), R and R1 are phenyl groups.
1-position thiophosphinic acid ester derivative. 4. The thiophosphinic acid ester derivative at the C-1 position of sugar according to claim 1, which is a compound represented by the formula % (wherein Bn represents a benzyl group). 5. A thiophosphinic acid ester derivative at the C-1 position of a sugar according to claim 1, which is a compound represented by the formula (in the formula, Bn represents a benzyl group). 7, a compound represented by the formula (wherein Bn represents a benzyl group), which is a thiophosphinic acid ester derivative at the C-1 position of a sugar according to claim 1, which is a compound represented by the following formula: A C-1-position thiophosphinic acid ester derivative Q8 of a sugar according to claim 1, which is a compound represented by the formula % (wherein Bn is a benzyl group and Ac is an acetyl group). A C-1-position thiophosphinic acid ester derivative according to claim 1. 9. A thiophosphinic acid ester derivative at the C-1 position of a sugar according to claim 1, which is a compound represented by the formula (in the formula, ph represents a phenyl group) 10, a compound represented by the formula (in the formula, Bn represents a benzyl group) The thiophosphinic acid ester derivative at the C-1 position of a sugar according to claim 1, which is a compound represented by the group Ph represents a phenyl group. 11 General formula (II) (wherein R is -H, -C bird, -CH,OH, -OH. -CHoH-CH,OH, -OCH,Ph, -0CO
C horse. -0CR,, -0CR,0CPh,, -C horse OCR,P
h. -CH,0COCR,, -NHCOCH,, -CH(O
CR, Ph) C bird OCH, Ph , -CH (OCOC horse) CH, 0 COCH,. -CHoHCH,0CPh,,)C(Chorse)t,)c
Hph. -CH0CH*OC(CHs)t, -CH0Cbird0C
I (Ph no Izu Lm-----"Shi-1111"
(however, ph represents a phenyl group) R,,R
, represents an unsubstituted or substituted alkyl group or aryl group. ) A thiophosphinic acid ester derivative at the C-1 position of a sugar. 12. The sugar C according to claim 11, wherein R8 and R2 in the general formula [■] are methyl groups.
-1-position thiophosphinic acid ester derivative. 13. Sugar C-1-position thiophosphinic acid ester derivative 14, formula (78 (in the formula A thiophosphinic acid ester derivative at the C-1 position of a sugar according to claim 11, which is a compound represented by the formula (Bn represents a benzyl group) (wherein Bn represents a benzyl group and Ph represents a phenyl group). )
The thiophosphinic acid ester derivative at the C-1 position of sugar according to claim 11, which is a compound represented by: 16. A sugar having a hemiacetal bond at the 0-1 position is reacted with a strong base, and then the general formula [■] Tori (where Tori is an unsubstituted or substituted alkyl group or aryl group, o'y': indicates i atom)
It is expressed as A method for producing a thiophosphinic acid ester at the C-1 position of a sugar, which comprises reacting a halogenated phosphinothioyl. 17. The production method according to claim 16, wherein the halogenated phosphinothioyl is halogenated dimethylphosphinothioyl. 18. The manufacturing method according to claim 16, wherein the halogenated phosphinothioyl is halogenated dimethylphosphinothioyl. 19. The manufacturing method according to claim 16, characterized in that n-butyrrhizicum is used as the strong base. 17. The manufacturing method according to claim 16, characterized in that thallium ethoxide is used as the 20° strong base.