JPH04134091A - Production of trehalose isomer - Google Patents

Abstract

PURPOSE:To easily and separately produce the subject iso- and neotrehalose derivatives at the same time by reacting two specific kinds of compounds with each other and subjecting the reaction product to intramolecular rearrangement and deacetylation. CONSTITUTION:Compounds of formula III and formula IV are produced by reacting compounds of formula I (Ac is acetyl) and formula II in the presence of S-collidine preferably in a solvent. The compound of formula III and/or formula IV are converted to the compound of formula V or formula VI by the intramolecular rearrangement in a solvent in the presence of trimethylsilyltrifluoromethane sulfonate. The obtained compound of formula V or formula VI is deacetylated by treating with NaOCH3 in THF solvent to obtain isotrehalose of formula VII from the compound of formula V and neotrehalose of formula VIII from the compound of formula VI.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention relates to a method for producing isotrehalose or neotrehalose, which is an isomer of trehalose.

(Prior Art) α, α-1 levalose is an important substance as a sugar skeleton of mycolic acid ester of trehalose called code factor and as a carbohydrate raw material for other physiologically active substances.

In order to investigate the relationship between the structure and activity of physiologically active substances, it is necessary to convert the sugar skeleton into isotrehalose (β, β-trehalose) or neotrehalose (α, βl-levalose).

In ancient times, as a method for producing isotrehalose, ft,)
1. Scl+lubach et al.'s method [Z, PI+ysi
o1. Chem, 213 (1932) 83], and methods for producing neotrehalose include stomach, N, H
The method of Aworth et al., Journal of Chemical
Society (Jou+・nal or Chemica
(1931) 2B47
]It has been known.

Those methods are as follows.

H, 11,5 Chlubach et al.'s method (1932)
Isotrehalose (hereinafter referred to as margin) Method of ~S, N, IIawnrt, h et al. (1931
) ■ Neo 1 Levalose Recent methods of producing isotrehalose include S, J,
The method of Cook et al. [Journal of Carbohydra-1-Chemistry
Cbemistry), L (1984) 343
], and the manufacturing method of Neneo Lebarose is as follows.
J, Yosl+ Imura et al.'s method [Chemistry
Letters (Chemistry LeLL-ers)
, (1983) 319] has been reported.

Those methods are as follows.

S, J. Cook et al.'s method (1984) = 10 J, Y (l S II i m ura et al.'s method (1983) (wherein, Bn represents a benzyl group) (In the formula, Bn represents a benzyl group) However, the conventional pJ3P+ method for isotrehalose or neotrehalose is unable to simultaneously produce isotrehalose derivatives and neo1 helevalose derivatives, resulting in a large number of problems. Even if one tried to obtain the other, there was no way to advantageously obtain the other from the production intermediate of the one, and there was no other way than to produce the other from the beginning.

Therefore, it has been desired to develop a method that can simultaneously produce iso-1-levalose derivatives and neo-1-levalose derivatives, and can produce isotrehalose or neotrehalose individually with simple operations.

(Means for Solving the Problems) As a result of intensive research to solve the problem described in item 1, the present inventors have discovered that isotrehalose derivatives and neotrehalose derivatives can be produced by intramolecular rearrangement of orthoesters. Furthermore, they succeeded in producing isotrehalose or neo-1 helevalose individually with simple operations, and also succeeded in producing a mixture of isotrehalose and neotrehalose. , we have completed the present invention.

The contents of the present invention will be explained in detail below.

Compound (3) and compound (4) are the following: A-1\
As shown in 1, one combination of known compounds (13 "K;
Gejala & Link, Journal of American Chemical Society (J, 8m, chem,
soc, ), 622-(1940) 917. ] and the compound e+ (2>
[C, M, McCloskey et al., Journal of the American Chemical Society (, IAm,
Chem, Soc.), 4-(1944) 349. It can be synthesized from

This synthetic reaction is performed, for example, by reflating (8gO802CF3) to silver 1 in a medium such as 1,2-dichloroethane.
), and more preferably in the presence of S-collidine.

In addition, this synthesis reaction is carried out under an atmosphere such as N2 at 50 to 50
It is preferable to carry out the reaction at a temperature of 1 minute to 24 hours while stirring the reaction system.

Furthermore, this synthetic reaction can also be carried out by refluxing in 1,2-dichloroethane in the presence of triethylamine.

Compound (5), which is an isotrehalose derivative, and f-jion 1-phrase (6), which is an odorevalose derivative, can be synthesized by intramolecular rearrangement of 1-hyphen (3) or compound (4).

This intramolecular rearrangement may occur, for example, to trimethylsilyltrifluoromethanesulfonate in a solvent such as 1,2-dichloroethane. ) is preferably carried out.

Further, this rearrangement reaction is preferably carried out at a temperature of -50 to 50°C for 1 minute to 24 hours while stirring the reaction system.

Isotrehalose (7) can be synthesized by deacetylation of compound (5).

This deacetylation is preferably carried out, for example, by treatment with NaOCH3 in a methanol-tetrahydrofuran (hereinafter sometimes abbreviated as THF) solvent.

Furthermore, neo-1 levalose (8) can be synthesized by deacetylating compound 1-revalose (6).

This deacetylation is carried out in a solvent such as methanol with N a
OC. This can be carried out by processing with H3]
3 It's feminine.

Moreover, if necessary, isotrehalose and neo-1.levalose can be simultaneously produced from the isotrehalose derivative and neotrehalose derivative σ) mixture.

Note that Compound 1 (3) and Compound (4) synthesized in the above steps are new compounds.

(The following is a blank space) (Example) The content of the present invention will be described in more detail with reference to Examples below, but the scope of the present invention is not limited to the following Examples.

Example-1 [Compound (1) + (2) → (3) + (4
)] 100 mA for 10.3 g of Ag08O2CF3
1,2-dichloroethane was added, and the system was purged with nitrogen. Next, 11.0 g (31.6 mmol) of compound (2) dissolved in 1,2-dichloroethane of 110 m(!)
and 5.3 m (40.1 mmol) of S-collidine were added,
Cooled to 0°C.

Then, 15.0 g (36.5 mf) of the compound (1) dissolved in 150 aQ of 1,2-dichloroethane was added dropwise.

The reaction was carried out at 0°C → room temperature for 19 hours. After the reaction, 1ρ
of Cll2Cρ2 was added, filtered through Celite, treated with hydrochloric acid,
After treatment with sodium bicarbonate and washing with water, the organic layer was dried with MgSO4.

After filtration, concentrate under reduced pressure and transfer the residue to 1.8k silica gel.
g column (eluent: Kurokame Kopormoor 7 tons = 20
:1. ) to separate and purify 7.0g of compound (3).
(yield 32.7%), and 10.0 g (yield 46.7%) of compound (4) were obtained.

[Properties of compound (3)] 'rLCRf=0.34 (Li00pormacetone=1
0:1) Elemental analysis (as C2sH380+9) Calculated value C,
49,56・I-15,64 measurement value C, 49,68
; H, 5,64 specific optical rotation [α]o+17.7° (C3,01, Cl-IC, Q3) 111-NMR (CDCj, ) 5.692 (cl, Ill, J5.3711z, ll-
1a) 4.775 (d, Ill, J8.0611z, l
t-1b).

2.100 (s, 311.8c), 2.094 (s, 6
11.2AC)1'', C-NMR (CIICj3) 97.1 ('Jc++181.911..C-1a).

94.6 ('Jco161.I11..C-1b).

[Properties of compound (4)] TLCr? , f=0.41 (chloroporno, ace1-
-10・1) Elemental analysis (as C281-138019) Calculated value
C, 49, 56, 1-1, 5, 64 measurement value c, 4
9.26・ 11 5.59 Specific optical rotation [α]o+73
．． 7゜(C3,01, Cl-IC, Q3) IN-N14R(CDCj,) 5.785(d, ILI,, J5.3711z, H-1
a＞.

5.307((+, Ill,, 13.91tlz, l
l-1b) 2.114 (s, 311.Ac), 2.09
9(s, 6+I, 2AC) 2.079(s, 31+, A
c), 2.033 (s, 6tl, 2Ac).

2.003(s, 31(, 80).

0. 1. 753(s, 3H, O; C-Cl13)"C-N
MR (CDCj3) 97.3 (', Icu183.ill,, C-1a).

90.5 ('Jco172.IH2, C-1b) Example-2 [Compound (3) - Compound (s) + (0)] 1.8.6 g of compound (3) was added to 300 g of 1.2-dichloroethane
TMSOTf5 was dissolved in mQ and cooled to 0 °C.
．． 3 m and Q were added and stirred for 1 hour. After the reaction is complete, C
l2Cρ21, Q was added, and after baking soda treatment, the organic layer was mixed with Mg5
Dry with O4.

After filtration, reduce and crush the residue to 1°8 kg of silica gel.
column (eluent: chloropormoacetone = 10:1
) and crystallized with ethyl acetate solvent to obtain 7.21 g of compound (5) (yield 38.8%).
), 0.47 g (yield 2.5%) of 1 Hibiscus (6) was obtained.

[Property 1 of compound (5) TLCR, f = 0.33 (chloroboramacetone-10
: ], ) Elemental analysis (as C2s038019) Calculated value C,
49,')6; tl, 5.64 measured value C, 4
9,26・[(5,59Specific optical rotation [α].-11,
1° (C1,75, Cto1c, (7<) [Literature value -15,5°, the literature of S, J, Cook et al. (C5,4, CHCff13)] Melting point 178-180°C "Literature value 1.81.5~183°C1 The literature is the same"-]'
l-NMR (CDCj3) 4.902 (d, J7.33) Iz, H-1, H-1'
) 2.106, 2.062, 2.027, 2.009 (
4s, 4AcX 2) "Literature value 4.9 (d,, J811
z, Ito1, Illo)1 References are the same"2]"C-N1
dR (CIICJJ 96.6 (C-1, C-1> [Properties of compound (6)] TLCR, f = 0.35 (Rl''? +:'? Polacetone - 10:1) Elemental analysis (as C2883FIO+9 )31 calculation value
C, 49, 56, H, 5, 64 measurement value C, 49, 58
: tl, 5.65 specific optical rotation [α]o +74
．． O.

(C1, 00, Cl-IC, Q3) "Literature value +82° (c5, ClIC evening,), the above V
1. N, IIawnrLh et al.] Melting point 1385-1,40.5°C [Literature value 14
0 to 141°C, the literature is the same as above.It-NMR (CDCj
,,,) 5.348(d, 1.11.J3.6611z, a-1
1-1,)4.704(d,ltl,,JR,0611
z, β-8-1>2.119, 2.092, 2.040
．． (3s, 911, 3Ac) 2.038 (s, 611
2AC>, 2.027(S, 3+1.8()2.01
4(s, 6H, 2AC) "C-NMR (CDCj3) 100.0 ('Jcu16],, 1) 1z, β-C-1
)96.9('JCI+175.8117.a-C-
) Example-3 [Compound (4) → Compound (5) +(
6)] 10.04 g of compound (4) was dissolved in 180 mρ of 1,2-dichloroethane, cooled to 0°C, and heated to 1°C.
MS OT f 2 , 9 mQ was added and stirred for 1 hour.

After the reaction was completed, CH2C424 and OOmQ were added, and after treatment with sodium bicarbonate, the organic layer was dried with MgSO4.

After filtration, concentrate under reduced pressure and transfer the residue to 16 kg of silica gel.
column (eluent: chloroporum-acetate),
O: 1) to separate and purify the compound (5), and crystallize from an ethyl acetate-ether solvent to obtain compound (5), 62 g (
074g of compound (6) (yield 7.4%)
%) Good value.

Example-4 [Compound (5) = (7)] Compound (5)
4.03g methanol 250tnQ and THF15m
Q was dissolved in a mixed solvent, 1N-Na0CH, 1 mΩ was added thereto, and the mixture was stirred at room temperature for 19 hours.

After the reaction is completed, amber light (Amber light)
) IR, C-50 (manufactured by Rohm and Haas)
was added to OmQ, stirred for 20 minutes to neutralize, filtered through Celite, and concentrated under reduced pressure.

Gel filtration of the residue [Sephadex (5ephadex)]
G-25 (manufactured by Pharmacia) 30 OmQ, H2
Compound (7) was purified by 1.0] and crystallized from a water-acetone solvent. ．． 87g was obtained (yield 920%).

[Properties of compound (7)] TLCRf=0.26 (ethyl acetate-5-nol-water-8:4:2> Elemental analysis (C+2022011・I/2l-12 (as one) calculated value C, 41,02 : H, (1,6(
1 Measured value C, 40,83;
6 (C7,4, +420), the above-mentioned literature of S, J, Cook et al.] Melting point 1.30.5 to -1,37,0'c [Literature value 134-139°C5 literature is the same"-]'II -NMR
(D20.50°C) 4.817(d, J8.0611z, It-]-, H-
) [Literature value (24℃) 4.74 (d, J7.5
11z, Ill, Ill゛), literature is same as above] "C-NMR (D20) 100.0 (', Jco162.3Hz, C-],
C-1') Example-5 [Compound (6)→(8)] Compound (6)1. ．． 38 g was dissolved in 28 mQ of methanol, 4 mQ of IN-Na0CH3o was added, and the mixture was stirred at room temperature for 18 hours.

After the reaction is completed, Amberlite (AmberliLe)
2.4 nt9 of JRC-50 was added, stirred for 20 minutes to neutralize, filtered through Celite, and concentrated under reduced pressure.

The residue was dissolved in 4 mQ of water, treated with activated carbon, and concentrated under reduced pressure.

The residue was crystallized from a water-acetone solvent to obtain the compound (
8) was obtained in an amount of 436.3 mg (yield: 62.7%).

[Properties of compound (8)] TLCR, f=0.16 (i'it: acid ethyl-ethanol-water-8:4:2) Elemental analysis (as C+□H220,,・1120)
Calculated value C, 40,00; H, 6,71 Measured value C
, 40,04; H, 6,68 specific optical rotation [α]o+
84.8° (C1,00, H20) [Literature value +95° (C3,55,1120), above W
, N, 11.1w or th et al. 1 +11-NMR (I) 20,50°C) 5.244 (d, 1N, +3.66Hz, σ-II -
], )4.655(d,Ill,,+7.8211z
, β-t1) + 3C-NMR (D20) 103.8 ('Jcn161.111z, β-C-1)
101.1('Jco170.9Hz, a-C-1>(
Effects of the Invention) By carrying out the present invention, isotrehalose derivatives and neotrehalose derivatives can be produced simultaneously, and isotrehalose or neotrehalose can be produced individually by simple operations.

Patent applicant: Towa Kasei] Nigyo Co., Ltd.

Claims (1)

[Scope of Claims] 1 (a) A compound (1) represented by the following formula (I), ▲Mathematical formula, chemical formula, table, etc.▼(I) (In the formula, Ac represents an acetyl group); The following formula (II), ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) (In the formula, Ac represents an acetyl group.) By reacting with the compound (2) shown by the following formula (III), ▲There are mathematical formulas, chemical formulas, tables, etc.▼(III) (In the formula, Ac represents an acetyl group) Compound (3) and the following formula (IV), ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (IV) (In the formula, Ac represents an acetyl group.) Step of producing a compound (4) represented by the following formula, (b) By intramolecular rearrangement of the compound (3) and/or the compound (4), (V), ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (V) (In the formula, Ac represents an acetyl group.) Compound (5) shown by the following formula (VI), ▲ Numerical formulas, chemical formulas, tables, etc. ▼(VI) (In the formula, Ac represents an acetyl group.) The process of producing the compound (6) represented by (c) Deacetylation of the compound (5) and isotrehalation process. A method for producing a trehalose isomer, characterized by: 2 (a) Compound (1) represented by the following formula (I), ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, Ac represents an acetyl group), and the following formula (II), ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) (In the formula, Ac represents an acetyl group.) By reacting with the compound (2), the following formula (III), ▲Mathematical formulas, chemical formulas, tables, etc. ▼ (III) (In the formula, Ac represents an acetyl group.) Compound (3) represented by the following formula (IV), ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (IV) (In the formula, , Ac represents an acetyl group) (b) By intramolecular rearrangement of compound (3) and/or compound (4), the following formula (V), ▲ Formula , chemical formulas, tables, etc. ▼ (V) (In the formula, Ac represents an acetyl group) Compound (5) and the following formula (VI), ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (VI ) (In the formula, Ac represents an acetyl group.) (c) A step of deacetylating compound (6) to produce neotrehalose [compound (8)] A method for producing a trehalose isomer, comprising the following steps.