JPS6160693A - Preparation of daunosamine derivative - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as an intermediate for an antitumor agent in high yield in high efficiency, by debenzoylating novel methyl- O-benzoyl-trifluoroacetamido-trideoxy-alpha-D-erythrohe-xopyranoside. CONSTITUTION:Part of methylidene group of methyl 4-O-benzoyl-3-trifluo roacetamido- 2,3,6-trideoxy-alpha-D-erythr-ohexene-5-pyranoside shown by the formula I is reduced to give novel methyl 4-O-benzoyl-3-trifluoroacetamido 2,3,6-trideoxy-alpha-D-erythr-ohexopyranoside shown by the formula II (Ph is phenyl) is debenzoylated, to give the aimed methyl 3-trifluoroace tamido-2,3,6-trideoxy-alpha-D-erythrohexopyranos-ide shown by the formula III.

Description

[Detailed description of the invention] The present invention relates to a novel method for producing daunosamine derivatives.

Daunosamine is an antitumor antibiotic called daunomycin (U.S. Pat. No. 3,616,
No. 242) and adriamycin (U.S. Pat.
, 590,028). Chemically modifying these antibiotics to find powerful, highly safe derivatives with reduced side effects. Various attempts have been made to chemically synthesize anthracycline derivatives. Daunosamine derivatives are extremely useful compounds as starting materials.

Conventionally, as a method for producing daunosamine, the method of Wong et al. (Can, J. Chcm, and 3144 (
1975) ).

The method of Tsuiman et al. (Angew, Chem, In
t, Ed, EngL.

17.682 (1978)), the method of Matsumoto et al. (Bull
, Chem.

Soe, Jpn, 52.2731 (1979)), the method of Grete et al.
103.3956 (1981)) is known as a method for obtaining racemic daunosamine, but both have low yields and are often obtained as a mixture of various epimers. It has the disadvantage that it must be divided by division.

On the other hand, as a method for synthesizing only the L-body,! 3! Production methods using L as a starting material are known, but they have various drawbacks, such as the method of Gutsman et al.
Chem, Soc, Chem, Comn,, 9
73 (1967)) uses the very expensive L-rhamnose as a starting material, has a low yield, and requires a large number of steps.
bohydr, Res, 59, 343 (1977)
) uses inexpensive glucose as a raw material, but it has problems due to the use of resin when introducing amino groups, the need for chromatographic separation and purification, and the large number of steps. Intermediate method (Unexamined Japanese Patent Publication No. 54-1
4913) uses inexpensive glucose as a raw material, but requires two lithium aluminum hydride reduction steps, uses mercury during methyl glyconde synthesis, and has a large number of steps. There are many things that can be mentioned.

In addition, as a method for synthesizing only the L-isomer, Horton et al. has described a relatively inexpensive method using monomannose as a starting material (Carbohydr, Res, 44.227 (1).
975)). The method of Horton et al. is an excellent method with a high yield and fewer purification steps. However, in order to produce anthracycline derivatives by condensing daunosamine with aglycone, it is necessary to convert daunosamine into a sugar halide represented by the formula 02%. Collection, page 59 (lecture number 1-14)) According to K, the methi/I/8-)lifluoroacetamide-2,3,6-)lysooxy-α-ri-erythro represented by the formula (9) Quinpiranoside can be produced according to the following formula.
Since the sugar hafide (2) can be produced in a relatively short process without going through daunosamine, Maeko's method can be used not only as a method for producing compound (9), but also as a method for producing sugar hafide (2) 9. It can be said that this is an excellent method.

However, even in this method, there is a restriction in terms of me because the intermediate is relatively unstable.

Under such circumstances, the present inventors investigated an efficient method for producing the sugar derivative represented by the above formula (9), and as a result, completed the present invention.

That is, the present invention provides methyl 4- represented by the above formula (7)
0-bency/L'-8-)lifluoroacetamide-
By reducing the methylidene group of 2,3,6-trideoxy-α-D-erythrohexene-5-bifunoside, methyl 4-0-bencyi/
v-3-trifloacetamide 2.3.6-)lysooxy-α-D-erythrohexobiranoside, and then subjecting compound (8) to a debenzoyl reaction to obtain the formula (9) This invention relates to a method for producing a sugar derivative represented by:

The raw material compound represented by the formula (7) and the formula (9)
) are all known (as described in Maegoko, biJ), but the present invention is characterized in that it passes through a novel intermediate represented by the above formula (8), and the present invention According to the method, compound (9) can be efficiently produced with good yield. The present invention will be explained in more detail below.

Methi, /I/ 4-0-benshii IV-3-)! J7～
Oroacetamide 2.3.6- ) Lysooxy-α-
The reduction of erythrohexene-5-biwonoside (7) can be carried out, for example, by hydrogenation methods. Examples of solvents used in the hydrogenation reaction include alcohol solvents such as methanol and ethanol, ether solvents such as THF and dioxane, and ester solvents such as ethyl acetate. is preferred. As the catalyst, a metal catalyst such as palladium or platinum or a catalyst prepared by adhering these to a carrier can be used, such as badge rum carbon, palladium-barium sulfate, etc., but palladium-barium sulfate is preferable. The intermediate (8) obtained in this way is much more stable and easier to handle than the above-mentioned intermediate (6). Furthermore, it is a feature of the present invention that no 5-shrimp body is produced in this reaction.

The debenzoylation of methyl 4-0-bency/l'-3-)lifluoroacetamide-2,3,6-)lysooxy-α-ri-erythrohexopifnoside (8) can be carried out, for example, in an alcoholic solvent or Although an alkali metal hydroxide such as sodium hydroxide may be reacted in a hydroalcoholic solvent, it is preferably carried out by reacting sodium methylate in methanol.

Methyl/
l/8-)lifluoroacetamido-2,8,6-drideoxy-α-D-erythrohexobiranoside (9), for example, by a known method (J.

Antibiotics, 32, 228 (1979))
According to the following reaction formula, sugar halide (2) can be obtained according to the following reaction formula, that is, compound (9) is heated under reflux in 25% acetic acid to remove the methyl group, and the compound is expressed as 200. 8-N-)lifluoroacetamidodaunosamine, and then, for example, when treated with trifluoroacetic anhydride, 1,4-di0-)lifluoroacetyl-3-N-)refluoro Sysaccharide halide (2) can be produced by obtaining acetamidodaunosamine and further reacting it with hydrogen chloride.

The raw material compound represented by the general formula (7) is known per se, and can be produced, for example, according to the following reaction formula. The production of methi-4,6-0-benzylidene-2-deoxy-α-D-erythrohexobyranoside 3-ulose (3) from 0 D-mannose (1), which will be explained below, is carried out using a known method. (Horton et al., Cabohydr, Ras,
, 44, 227 (1975)).

The conversion of the ketone compound (3) to the heptamine compound (4) can be carried out by the method of Horton et al., but it can also be carried out by using a reducing agent in the presence of an ammonium salt in a medium. As a reaction medium, alcoholic solvents such as methanol-1 ml ethanol, n-propano/I/, and isozolopanol, or apco/I'-based solvents and ether solvents such as tetofhydrofufuran and dioxane are used. A mixed solvent is used, preferably methanol. In addition, examples of ammonium salts include ammonium chloride,
Ammonium acetate, ammonium carbonate, etc. are used, and amthonium acetate is preferably used. ◇Furthermore, as a reducing agent, borohydride such as lithium polyhydride, sodium borohydride, lithium cyanoporohydride, sodium cyanoporohydride, etc. A compound is used, preferably lithium cyanoporohydride or sodium cyanoporohydride.

In this way, methi/L/3-amino-4,6-penzylidene-2,3-dideoxy-α-D-ribohexopyranoside (4) is produced in two steps via the conventional oxime. This method is characterized by being able to shorten the previous steps to one step and also to be able to manufacture it safely. .

Compounds (4) to (7) can be produced according to known methods (Maetaka et al., supra). For example 3
-Amino compound (4) was dissolved in an organic solvent with trifluoroacetyl to give methyl/l'4.6-penzylidene-3-trifluoroacetideamide-2.3-ditoxy-α-D.
- can lead to lipohexopifnond (5). Examples of reaction solvents include ethers such as ether, tetophhydrofuran, and dioxane, and halogenated fluorophores such as chloroform, methylene chloride, carbon tetrachloride, and ethylene chloride.
A system solvent such as pyridine, trifluoroacetyl dichloride, trifluoroacetic anhydride, etc. are used, but it is preferable to react with trifluoroacetic anhydride in methylene chloride. In addition to 5), 7% of the 3-bitolift oloacetamide compound is obtained, but the latter is insoluble in carbon tetrachloride and can be easily removed, and the reaction solvent in the next step is tetrachloride. 3-trifluoroacetamide obtained in this way (
The oxidative cleavage of 5) is performed in a halogenated furkyl solvent.
Preferably, carbon 9-tetrachloride is used in the previous step. When this reaction is carried out on a large scale, in addition to N-bromosuccinimide, barium carbonate, and Touch IR'
fjk α,α-azobisisobutyronitri~ is added to reflux the carbon tetrachloride solution, and the carbon tetrachloride solution of 3-trifluoroacetamide (5) obtained in the previous step is added to this. In other words, completion of the reaction can be achieved.

Dehydrobromination of the obtained methi/I/4-0-bency/l/-6-bromo 3-trifluoroacetamide 2.8.6-drideoquicou α-D-ribohexobifnoside (6) The reaction is carried out using silver fluoride, diazabicycloundecene, etc. Preferably silver fluoride in pyridine is used.

The present invention will be specifically described below with reference to Reference Examples and Examples.

(Reference Example 1) α-D-meflL'mannopyranoside 8.92 g, dimethylformamide toxytoene 16.681y and p-to-enesulfonic acid 200? was added and heated at 70°C under reduced pressure (50-15
0wsHt) Heat and stir, and after the reaction is complete, add ice water 881
The number of crystals precipitated by injecting w and 5.80 kflC of baking soda into the reaction solution is 0.
Recrystallized from kf to 15.3kg Tsume'F-iv 2
,3.4.6-G0-benzily'J-(1-D-
Mannopyranoside was obtained 0 (yield 90%) melting point 108-
172°C (Reference Example 2) Methi/I/2.8:4.6-di-O-benzylidene-α
-D-mannopyranoside (3.87-) was added to 40 kg of dorofuran (VCfg) at -25 to -45°C to which 13.757 of n-butyl ivv ticumhexane solution was added, followed by stirring at the same temperature for 1.5 hours. 0 Ammonium chloride after the reaction 1. Ice water containing 69k, 60) The crystals precipitated by injecting the cfK reaction solution were washed successively with 3kf1 of water and 12 toluene powder, and when dried, methi/l/4,
6-0-benzylidene-2-deoxy-α-ri-erythrohexobiranoside 1. 85 k, was obtained.

(Yield 67%) FA point t7o-i7t°C (Reference Example 3) Methyl/l'4,6-0-benzylidene-2-deoxy-
5.17 kf of α-ri-erythrohexopifnosite and 14.016 kf of ammonium acetate were added to methano-plookfK.
95% 5% sodium borohydride was added to this at room temperature, and the mixture was stirred for 4 hours.
After making the mixture alkaline by adding % aqueous sodium hydroxide solution, the mixture was extracted three times with 26 kF of methylene chloride. The organic layer was washed with 26 kf of brine, extracted twice with 4% acetic acid at 22°C, and made alkaline with 10% sodium hydroxide.
Furthermore, chloride ≦ H... By extracting 3 times with 2 to 20%, drying over anhydrous magnesium sulfate, and filtering, A methylene chloride solution of xopyranoside (60 kg) was obtained (49% yield). The melting point of (4) was 112-118°C (Reference Example 4). -benzylidene-2,3-dideoxy-α-D-ribohexopyranoside methylene chloride solution 5 5. Add pyridine 400P to O kp, and add trifluoroacetic anhydride 2, under ice water cooling.
83 hours of water was added, and the mixture was allowed to react at the same temperature for 30 minutes. Add heavy IJ to the reaction solution 4. The methylene chloride layer was washed with 32 kf of water, and the solvent was eluted.The resulting residue was washed with 86 carbon tetrachloride and filtered to give methyl 4,6-0. Penzyritene-3-trifluoroacetamide-2,3-dideoxy-α-D-
A carbon tetrachloride solution of lifohexobiranoside was obtained. (Yield 90%) The melting point of (5) is 65-75℃NM
R(90MHz, CDCJ, )δ(ppm) 2
．． 00 (2H, m), 8.35 (IH, s), 1.6-
3.85 (2H, m), 3.8-4.85 (4H, m)
7.3 (5H, bs), 7.7 (IH, bs) (Reference Example 5) Methyl 4.6-0-benzylidene-3-trifluoroacetamide-2,3-dideoxy-α-D-ribohegyso Bionondo's hypochlorite tetrachloride solution 645 kl KN-bromosuccinimide 30? and barium carbonate 412,
After cooling the reaction solution by heating under reflux for 1 hour, insoluble matter was removed with F, and the obtained carbon tetrachloride E8 solution was added to a 20% hypo aqueous solution 200
mj twice, 200m4 of saturated sodium bicarbonate solution, then 200ml of saturated saline solution
The organic layer was washed successively with 0.0 m of water, and the organic layer was concentrated. D-ribohexopyranoside 56, 2f was obtained o('I's: rate 92%) melting point tos-iio'cNM
R (9 0 MHz, CDC I, ) δ (ppm
) 2.0-2.25 (2H.m).

3, 4-17 (2H.m), 3.50 (3H.s)
, 4.0-4.4 (IH.

m), 4.5-5.3 (3H, m), 7.8-8
．． 1. (6H, m) (Reference Example 6) The previously obtained methyl 4-0-benzoyl-6-promo 3-trifluoroacetamide-2.

3,6-) Lysooxy-α-D-ribohexo-diff/
c) '148f'e pyridine 8. Dissolve in 2 kv,
Silver fluoride 1482 was added and stirred at room temperature for one day.The 0 reaction solution was poured into ether 6kp, silica/I/2862 was added, filtered, and the OP solution was concentrated to obtain ether/I/11.
It was diluted with water, washed twice with saturated copper sulfate aqueous solution 11, dried with anhydrous magnesium sulfate, and washed with p supertemperature W. Upon elution, methyl A/4-0-benzoyl-8-fluoroacetamide-2.3.6-)lysooxy-α-D-erythrohexene-5-bifunoside 1002 was obtained (yield: 8
6%) Melting point 69-78℃ NMR (90MHz, CDCj13) δ (pam)
IJ5-235 (2H, m).

8, 48 (3H, s), 4.5-5.0 (4H, m),
5.5-5.75 (LH, m), 7.3-8.2 (
6H,m) (Example 1) Noside (8) Methi/I/4-0 pencey/L'-3-)lifluoroacetamide-2.3.6-dolideoxy-α-D-erythrohexene-5-pyranoside 50ft-ethyl acetate 5
00mj, 10% palladium-barium sulfate 1
6j' was added and stirred for 1 hour under a hydrogen stream at normal pressure and room temperature.
When filtered and distilled off, methyl 4-0-pency, Az-3
-) Lifluoroacetamide-2.3.6-trideoxy-α-ri-erythrohexobiranoside 40? was gotten.

(Yield 80%) NMR (901v11(z, CDCJ, )δ
(ppm) 125 (8H, d, J = 6.2Hz) 1,
7-2.2 (2H, m) + 8.57 (3
I(,s), 3.84 (IH.

dd, J=6.5Hz), 4.1-4.6(21(,
m), 5.28 (IH.

d, 2Hy, ), 6.62 (IH, bd, J=8H
z), 7, 3-7.7 (3H.

m), 7.9-8.2(2H,m) (5iI! Example 2) Methyl/L'4-0-benzoyl-3-trifluoroacetamide-2.3.6-drideoxy-α-D- Dissolve erythrohexopyranoside 502 in methanol/11500 ~, and add 1 5,7N-sodium methylate at room temperature.
After adding 1.8 F and stirring for 1 day at the same temperature and making it neutral by adding 0 acetic acid, the reaction solution was distilled off, and after adding and dissolving acetone 1Δ, it was dried over anhydrous magnesium sulfate 102. After f & concentration, the resulting residue was washed with 500 mJ of n-hexane,
After drying, methyl 3-trifluoroacetate (2.3.6-)
was gotten. (Yield 97%) Melting point 145-147℃ NMR (90MHz, CDC11,) δ(pl)m
) 1.32 (3H, d, J=132Hz) 1.5-2
．． 25 (2H, m), 2.38 (IH, d, J = 10H
y, ) 3.55 (3H, s ), 3.4-3.8 (2H
, m> , 4.42 (IH.

Claims (2)

[Claims] (1) Methyl 4-O-benzoyl-3-trifluoroacetamide-2,3,6-trideoxy- expressed by the formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (In the formula, Ph represents a phenyl group.) α-D
-Methyl 3-trifluoroacetamide-2 represented by the formula ▲Mathematical formulas, chemical formulas, tables, etc.▼ characterized by subjecting erythrohexopyranoside to a debenzoylation reaction
, 3,6-trideoxy-α-D-erythrohexopyranoside. (2) Methyl 4-O-benzoyl-3-trifluoroacetamide-2,3,6-trideoxy- expressed by the formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (In the formula, Ph represents a phenyl group.) α-D
-By reducing erythrohexene-5-pyranoside, methyl 4-O-benzoyl-3-trifluoroacetamide, which is represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (in the formula, Ph represents a phenyl group) -2,3,6-trideoxy-α-D
-Methyl 3-trifluoroacetamide-2 represented by the formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼, which is characterized by obtaining erythrohexopyranoside and then subjecting it to debenzoylation reaction.
, 3,6-trideoxy-α-D-erythrohexopyranoside.