JPH0959218A - L-lactic acid oligomer derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound not containing a homologue different in the polymerization degree, namely having a constant chain length, and useful for biocompatible materials and drug delivery systems as a standard substance for determining the biological activities of plants or animals. SOLUTION: A compound of formula I (R<2> is H, an alkyl, an aryl; R<1> is R<2> , an acyl, a silyl; R<1> and R<2> are not simultaneously H; n is 0-20). For example, a compound of formula II (TBDMS is t-butyldimethylsilyl). The exemplified compound is obtained by treating L-lactic acid with TBDMS-Cl, treating the obtained product protected in both the OH group and the carboxyl group with oxalyl chloride and dimethylformaldehyde, reacting (A) the obtained OH- protected acid chloride with (B) a carboxyl group-protected L-lactic acid, removing only the carboxyl group-protecting group from (Z) the obtained compound of formula III to obtain (C1 ) the compound, removing only the OH-protecting group from the compound of formula III to obtain (C2 ) the compound, and subsequently condensing the compound C1 with the compound C2 in the presence of a condensing agent.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel L-lactic acid oligomer derivative.

[0002]

2. Description of the Related Art The growth promoting effect of lactic acid on plants was first reported in an experiment using carrot callus in 1924 (Blumenthal F and Meyer P (1924) Uber durch Acidu).
m lacticum erzeugte Tumoren auf Mohrrubenscheiben.
ZfKregsg.21: 250-252.). Experiments were also conducted on other plants, such as marigold, sunflower and sugar cane, and the growth promoting effect of lactic acid was observed (Hild
ebrandt AC, Rikker AJand Watertor JI (1954) Growth
and Inhibition of tissue cultures on mediawith di
fferent concentration of organic acids. Phytopatho
logy 44: 422-428.). Since lactic acid oligomers are mixed in the aqueous lactic acid solution, active research is being conducted to investigate the main body of its activity, and the main body of the plant growth promoting substance is L-lactic acid, not the lactic acid monomer. (Alan M. Kinnersley, Taylor
C. Scott III, John H. Yopp and Gerge H. Whitten (199
0) Promotion of plant growth by polymers of lactic
acid. Plant Growth Regulation 9: 137-146.).

As described above, L-lactic acid oligomer is a useful substance having a plant growth promoting action.

A conventional technique for obtaining a lactic acid oligomer is to separate and purify a mixture of oligomers obtained by heating lactic acid by column chromatography to obtain a fraction of each polymerization degree. However, it is difficult to obtain a pure oligomer by the method of fractionating the oligomer mixture with a gel filtration column or the like. This is especially true for highly polar substances. Therefore, when the biological activity and the like are examined using the oligomer obtained by the conventional separation and purification method, the purity of the oligomer is generally insufficient. Further, if it is not a pure oligomer, it is difficult to freely perform its chemical modification.

[0005]

An object of the present invention is to provide a novel L-lactic acid oligomer derivative which can be obtained as a pure compound.

[0006]

The L-lactic acid oligomer derivative of the present invention is represented by the following general formula (I):

Embedded image Here, R ¹ represents H, an alkyl group, an aryl group, an acyl group or a silyl group, R ² represents H, an alkyl group or an aryl group, provided that R ¹ and R ² are both H None, n is an integer of 0 to 20.

The present invention will be described in detail below.

Examples of the alkyl group as R ¹ in the general formula (I) include methylthiomethyl (MTM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM) and (4-methoxyphenoxy) methyl. (P-AOM), (4-methoxyphenyl)
Methyl, t-butyldimethylsiloxymethyl, t-butyldiphenylsiloxymethyl, 2,2,2-trichloroethoxymethyl, 2,2,2-trichloroethyl, tetrahydrothiofuranyl, allyl, 1-ethoxymethyl, 1-ethoxy Protecting groups such as ethyl, benzyl, substituted benzyl, 2- (trimethylsilyl) ethoxymethyl (SEM) and the like can be mentioned. Of these, t-butyldimethylsiloxymethyl, t-butyldiphenylsiloxymethyl, and 2- (trimethylsilyl) ethoxymethyl groups are introduced more mildly,
It is preferable because it can be deprotected.

The aryl group as R ¹ includes, for example, a substituted or unsubstituted phenyl protecting group,
Examples of the substituent in this case include a p-methoxy group and the like.

Examples of the acyl group as R ¹ include, for example,
Monochloroacetyl, dichloroacetyl, methoxyacetyl, phenoxyacetyl, levulinoyl, methoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-
Examples of the protective group include (trimethylsilyl) ethoxycarbonyl and allyloxycarbonyl. Of these,
Monochloroacetyl and levulinoyl groups are preferable because they can be introduced and deprotected more mildly.

The silyl group as R ¹ is, for example,
t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), triisopropylsilyl (TIPS), dimethylthexylsilyl (TD
S), triphenylsilyl (TPS) and like protecting groups. Of these, t-butyldimethylsilyl, t
A -butyldiphenylsilyl group is preferable from the viewpoint of easy availability of raw materials, introduction and deprotection.

Examples of the alkyl group as R ² in the general formula (I) include methylthiomethyl, 2- (trimethylsilyl) ethoxymethyl, benzyloxymethyl,
Phenacyl, p-bromophenacyl, N-phthalimidomethyl, 2,2,2-trichloroethyl, allyl, benzyl,
Protecting groups such as substituted benzyl can be mentioned. Of these,
Phenacyl, p-bromophenacyl, 2,2,2-trichloroethyl, benzyl, and substituted benzyl groups are preferable because they can be introduced and deprotected more mildly.

The aryl group as R ² includes, for example, a substituted or unsubstituted phenyl protecting group.

In the present invention, R ¹ and R ² are both H
While it is not to be, unless at least one of R ¹ and R ² is H, R ¹ and R ² may be different and the same.

A preferred combination of R ¹ and R ² is that R ¹ is t-butyldimethylsiloxymethyl, t-butyldiphenylsiloxymethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (trimethylsilyl) ethoxycarbonyl. , T-butyldimethylsilyl,
Any one of t-butyldiphenylsilyl, triisopropylsilyl, dimethylthexylsilyl and triphenylsilyl groups, wherein R ² is phenacyl, p-bromophenacyl, N-phthalimidomethyl, 2,2,2-trichloro. One of an ethyl group, and
R ¹ is methylthiomethyl, benzyloxymethyl, p
-Methoxybenzyloxymethyl, (4-methoxyphenyl) methyl, 2,2,2-trichloroethoxymethyl, 1-
Ethoxyethyl, benzyl, substituted benzyl, 2,2,2-trichloroethyl, monochloroacetyl, dichloroacetyl, levulinoyl, 2,2,2-trichloroethoxycarbonyl, or an allyloxycarbonyl group, wherein R ² Is 2- (trimethylsilyl) ethoxymethyl, and the like.

Next, a method for synthesizing the lactic acid oligomer of the general formula (I) will be described. Generally, the L-lactic acid oligomer of the present invention comprises a hydroxyl group of an L-lactic acid monomer or oligomer in which a carboxyl group is protected by an R ² group and an L-lactic acid monomer in which a hydroxyl group is protected by an R ¹ group or It is obtained by condensing an oligomeric carboxylic acid or acid halide derivative, and those having an R ¹ group or R ² group of H are obtained by deprotecting a carboxyl group or a hydroxyl group.

That is, the method for synthesizing the lactic acid oligomer of the general formula (I) will be described below with reference to the synthetic scheme. In addition, this scheme shows an example of the synthesis method and does not limit the scope of the present invention.

The abbreviations in the scheme represent the following reagents: TBDMSCl = t-butyldimethylsilyl chloride DMF = N, N-dimethylformamide DIC = diisopropylcarbodiimide DMAP = 4-dimethylaminopyridine TBAF = tetra-n-butylammonium Fluoride HOAc = acetic acid

[0019]

Embedded image

Embedded image

First, L-lactic acid (1) is reacted with p-bromophenacyl bromide to obtain a compound (2) having a protected carboxyl group. Next, the hydroxyl group of compound (2) is protected with t-butyldimethylsilyl chloride to obtain compound (3).

On the other hand, from L-lactic acid (1) in three steps, that is, after protecting both of the hydroxyl group and the carboxyl group with t-butyldimethylsilyl chloride, oxalyl chloride and DMF are used.
To give an acid chloride derivative of L-lactic acid with a protected hydroxyl group, and reacting this acid chloride with the compound (2),
L-lactic acid dimer (4) is obtained.

Next, the p-bromophenacyl group of the dimer (4) is converted to the carboxylic acid (5) by treating with zinc in acetic acid. On the other hand, the t-butyldimethylsilyl group of the dimer (4) is converted to the alcohol (6) by using tetra-n-butylammonium fluoride in acetic acid. Both compounds thus obtained, that is, the dimeric carboxylic acid (5) and the dimeric alcohol (6) are condensed with diisopropylcarbodiimide to obtain L-lactic acid tetramer (7).

The t-butyldimethylsilyl group of the tetramer (7) was deprotected with tetra-n-butylammonium fluoride in acetic acid to lead to the tetramer alcohol (8), and the dimer carvone was obtained. Condensation with acid (5) (diisopropylcarbodiimide / methylene chloride) gives L-lactic acid hexamer (9).

Similarly, the obtained hexamer (9) was introduced into alcohol (10) (tetra-n-butylammonium fluoride / acetic acid) and condensed with dimeric carboxylic acid (5) (diisopropylcarbodiimide). / Methylene chloride) and L-lactic acid octamer (11) are obtained.

Further, the alcohol (2) having a protected carboxyl group and the dimer carboxylic acid (5) having a protected hydroxyl group are condensed (diisopropylcarbodiimide / methylene chloride) to obtain an L-lactic acid trimer.

Further, the p-bromophenacyl group of the tetramer (7) was treated with zinc in acetic acid to protect the hydroxyl group.
It is converted into a tetrameric carboxylic acid and the tetrameric carboxylic acid is condensed with alcohol (2) (diisopropylcarbodiimide / methylene chloride) to obtain an L-lactic acid pentamer.

Similarly, the p-bromophenacyl group of the hexamer (9) is treated with zinc in acetic acid to convert it to a hexamer carboxylic acid having a protected hydroxyl group, and the hexamer carboxylic acid and alcohol ( 2) is condensed with (diisopropylcarbodiimide / methylene chloride) to obtain L-lactic acid heptamer.

In this manner, the L-lactic acid dimer to octamer (n = 0 to 6) can be obtained as a pure compound. Thereafter, by repeating the same reaction, the 9- to 22-mer (n = 7 to 20) of L-lactic acid can be obtained as a pure compound.

In this synthetic method, in order to introduce the R ¹ group as a hydroxyl-protecting group, R ¹ X (where:
R ¹ is an alkyl group, an aryl group, an acyl group or a silyl group, and X is halogen (Cl, Br, I).

Deprotection of these R ¹ groups is carried out by appropriately deprotecting the L-lactic acid derivative according to the type of R ¹ , namely, tetra-n-butylammonium fluoride, thiourea, hydrazine acetate, It can be carried out by treating under conditions which do not affect other functional groups such as zinc-acetic acid, catalytic hydrogenation and mercuric chloride.

On the other hand, R as a protecting group for the carboxyl group
^Two groups are typically introduced by introducing R ² X (wherein R ² is an alkyl group or an aryl group, and X is a halogen (C
l, Br, I)) can be used.

For the deprotection of these R ² groups, the L-lactic acid derivative is appropriately deprotected depending on the type of R ² , that is, zinc-acetic acid, tetra-n-butylammonium fluoride or the like is used. It can be achieved by treating under conditions that do not affect the functional groups of.

Further, the hydroxyl group of the L-lactic acid monomer or oligomer in which the carboxyl group is protected by the R ² group is condensed with the carboxylic acid of the L-lactic acid monomer or oligomer in which the hydroxyl group is protected by the R ¹ group. In doing so, the condensing agent is not particularly limited, but generally, a carbodiimide type condensing agent such as diisopropylcarbodiimide or dicyclohexylcarbodiimide can be used. In this case, it is also preferable to use 4-dimethylaminopyridine or the like as a catalyst.

Further, a hydroxyl group of L-lactic acid monomer or oligomer whose carboxyl group is protected by R ² group and an acid halide derivative of L-lactic acid monomer or oligomer whose hydroxyl group is protected by R ¹ group are prepared. In condensing, the condensing agent is not particularly limited, but it is usually preferable to use a deoxidizing agent such as triethylamine or pyridine.

[0035]

EXAMPLES The present invention will be specifically described below with reference to examples, but the scope of the present invention is not limited to the following examples.

(Synthesis example 1)

Embedded image In a 2000 ml flask, 9.73 g of L-lactic acid (1
08.0 mmol), potassium hydrogen carbonate 10.81 g
(108.0 mmol) and p-bromophenacyl bromide 30.02 g (108.0 mmol) were added,
1600 ml of dried acetone was added, and the mixture was stirred under nitrogen gas at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure, suspended in ethyl acetate, and washed with water and saturated saline. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. The obtained crude product was recrystallized from ethyl acetate-hexane to obtain 25.24 g (yield 81%) of the desired product (2). (2) Rf = 0.49 (ethyl acetate: hexane = 1: 1) mp: 103-104 ° C. [α] ²⁰ _D −0.95 ° (C = 1.2, CH ₃ OH) MS (CI, isobutane ) 289 [M ( ⁸¹ Br) +1] ⁺ .
^{287 [M (79 Br) +1} ] + 1 H-NMR (270MHz, CDCl 3) δ: 7.6
30 to 7.800 (4H, m, aromatic protons: A
A'BB '), 5.579 (1H, d, 16.8Hz,
AB type A part), 5.340 (1H, d, 16.8H)
z, AB type B part), 4.500 (1H, q, 7.0H)
z), 2.799 (1H, br.s, OH), 1.56
4 (3H, d, 7.0Hz)

(Synthesis example 2)

[Chemical 6] In a 50 ml flask, the compound (2) obtained in Synthesis Example 1 was used.
To 970 mg (3.38 mmol), at room temperature, t-butyldimethylsilyl chloride 612 mg (4.06 mmo)
l) and 508 mg (7.46 mmol) of imidazole were added and dissolved in 1.3 ml of dried DMF. This was stirred under nitrogen gas at room temperature for 1 hour. This mixture was suspended in hexane and washed with water and saturated saline. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was subjected to silica gel column chromatography (Wako-gel
C-300. 75 g. The product was purified with ethyl acetate: hexane = 1: 9) to obtain 1.32 g of the desired product (3) (yield 97%). (3) Rf = 0.52 (ethyl acetate: hexane = 3: 17) mp: 39-41 ℃ [α] 20 D -15.1 ° (C = 0.70, CH 3 OH) MS (CI, isobutane ^{) 403 [M (79 Br)} +1] + 1 H-NMR (270MHz, CDCl 3) δ: 7.6
06-7.793 (4H, m, aromatic protons: A
A'BB '), 5.360 (1H, d, 16.2Hz,
AB type A part), 5.286 (1H, d, 16.2H)
z, AB type B part), 4.518 (1H, q, 7.0H
z), 1.515 (3H, d, 7.0Hz), 0.90
7 (9H, s, TBDMS), 0.128 (3H, s,
TBDMS), 0.120 (3H, s, TBDMS)

(Synthesis example 3)

[Chemical 7] In a 200 ml flask, 5.43 g of L-lactic acid (6
0.28 mmol), t-butyldimethylsilyl chloride 21.81 g (144.70 mol) and imidazole 18.11 g (266.01 mmol) were added and dissolved in 20 ml of dried DMF. This was stirred under nitrogen gas at room temperature for 18 hours. The mixture was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with hexane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude disilylated product. The obtained crude product was dissolved in 60 ml of methylene chloride and the temperature of the system was adjusted to 0 ° C., and then 10.72 g (84.46 mmo of oxalyl chloride).
1) was added, followed by 6 drops of DMF. After stirring at 0 ° C. for 1 hour, the mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure to obtain a crude product of acid chloride. 16. The resulting crude product was dissolved in 87 ml of diethyl ether and the temperature of the system was adjusted to 0 ° C., and then 34 ml of pyridine and the compound (2) obtained in Synthesis Example 1 16.
45 g (57.30 mmol) were added sequentially. 1 at 0 ° C
After stirring for an hour, the mixture was poured into a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with a 10% aqueous citric acid solution and a saturated saline solution. Then, the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (Wako
-gel C-300. 600 g. Ethyl acetate: hexane = 1:
9) and 24.35 g of the desired product (4) (yield 85%;
Three steps were obtained from L-lactic acid. (4) Rf = 0.42 (ethyl acetate: hexane = 3: 17) [α] ²⁰ _D −51.9 ° (C = 1.3, CH ₃ OH) MS (CI, isobutane) 475 [M ( ^{79 br) +1] + 1 H-} NMR (270MHz, CDCl 3) δ: 7.6
08-7.778 (4H, m, aromatic protons: A
A'BB '), 5.449 (1H, d, 15.9Hz,
AB type A part), 5.245 (1H, q, 7.2 Hz)
5.221 (1H, d, 15.9Hz, AB type B
Part), 4.416 (1H, q, 6.5Hz), 1.66
4 (3H, d, 7.2Hz), 1.453 (3H, d,
6.5 Hz), 0.919 (9H, s, TBDMS),
0.117 (3H, s, TBDMS), 0.090 (3
H, s, TBDMS)

(Synthesis Example 4)

Embedded image Compound obtained in Synthesis Example 3 in a 1000 ml flask
(4) Dissolve 5.43 g (11.47 mmol) in 370 ml of diethyl ether and add 19.70 ml of acetic acid at room temperature.
(344.13mool) was added. While stirring, 22.49 g (344.04 mmol) of zinc powder was added, and the mixture was stirred at room temperature for 2 hours. The mixture was filtered through a glass filter and the residue was washed with ethyl acetate to give a filtrate. The filtrate was extracted with saturated sodium hydrogen carbonate, citric acid was added to the aqueous layer to adjust the pH to 4-5, and the mixture was extracted with ethyl acetate. again,
The organic layer was extracted with a saturated aqueous sodium hydrogen carbonate solution, citric acid was added to adjust the pH to 4-5, and the mixture was extracted with ethyl acetate.
The organic layer was washed with brine and dried over anhydrous sodium sulfate. After concentration under reduced pressure, 2.47 g of the target product (5) (yield 78
%) Was obtained. (5) Rf = 0.26 (ethyl acetate: hexane = 3: 7) [α] ²⁰ _D −45.6 ° (C = 0.67, CH ₃ OH) MS (FAB +, m-NBA) 277 (M + 1) ) ⁺ , 299
(M + Na) ^{+ 1} H-NMR (270 MHz, CDCl ₃ ) δ: 8.6
70 (1H, br.s.COOH), 5.131 (1
H, q, 7.0 Hz), 4.403 (1H, q, 7.0)
Hz), 1.546 (3H, d, 7.0Hz), 1.4
49 (3H, d, 7.0Hz), 0.907 (9H,
s, TBDMS), 0.111 (3H, s, TBDMS
S), 0.087 (3H, s, TBDMS)

(Synthesis example 5)

Embedded image In a 100-ml flask, 3.50 g (7.39 mmol) of the compound (4) obtained in Synthesis Example 3 was dissolved in tetrahydrofuran (14.8 ml) at room temperature to obtain 5.08 m of acetic acid.
1 (88.74 mmol), 14.80 ml (1480 mmol) of a tetrahydrofuran solution of tetra-n-butylammonium fluoride having a concentration of 1M was sequentially added. After stirring at room temperature for 24 hours, the mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The crude product obtained by drying the organic layer over anhydrous sodium sulfate and concentrating under reduced pressure was subjected to silica gel column chromatography (Wako-g
ElC-300.80 g and ethyl acetate: hexane = 2: 8) were purified to obtain 2.13 g of the desired product (6) (yield 80%). (6) Rf = 0.49 (ethyl acetate: hexane = 1: 1) mp: 70-72 ℃ [α] 20 D -51.2 ° (C = 0.71, CH 3 OH) MS (FAB +, m -NBA) 359 (M ( ⁷⁹ Br) +1]
^{+ 1 H-NMR (270MHz,} CDCl 3) δ: 7.6
18 to 7.789 (4H, m, aromatic protons: A
A'BB '), 5.463 (1H, d, 16.4Hz,
AB type A part), 5.336 (1H, q, 6.8H
z), 5.256 (1H, d, 16.4 Hz, B part of AB type), 4.382 (1H, q, 7.0 Hz), 1.6
92 (3H, d, 6.8Hz), 1.494 (3Hd,
7.0 Hz)

(Synthesis example 6)

Embedded image In a 100 ml flask, 1.61 g (5.82 mmol) of the compound (5) obtained in Synthesis Example 4 was dissolved in 5.8 ml of methylene chloride, and the system was heated to 0 ° C. 500 mg (3.96 mmol) of diisopropylcarbodiimide here
Was added and stirred at 0 ° C. for 10 minutes. Synthesis Example 5 at 0 ° C.
952 mg (2.65 mmol) of the compound (6) obtained in 1. was dissolved in 5.8 ml of methylene chloride and added, and then 227 mg (1.86 mmol) of 4-dimethylaminopyridine was added. After stirring at 0 ° C for 30 minutes, the mixture was concentrated under reduced pressure. This mixture was suspended in ethyl acetate and washed with a 10% aqueous solution of citric acid, a saturated aqueous solution of sodium hydrogen carbonate, and a saturated saline solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. This mixture was suspended in hexane and filtered to remove the precipitate and remove the filtrate to obtain a filtrate. The crude product obtained by concentrating the filtrate under reduced pressure was subjected to silica gel column chromatography (Wa
ko-gel C-300. 130 g, ethyl acetate: hexane = 2:
The product was purified in 8) to obtain 1.5 g of the desired product (7) (yield 92%; from compound (6)). (7) Rf = 0.21 (ethyl acetate: hexane = 3: 17) Rf = 0.50 (ethyl acetate: hexane = 1: 3) [α] ²⁰ _D −87.5 ° (C = 1.3, _{CH 3 OH) MS (FAB +} , m-NBA) 617 (M (79 Br) +1]
⁺ . ^{561 (M- t Bu) + 1} H-NMR (270MHz, CDCl 3) δ: 7.6
25 to 7.768 (4H, m, aromatic protons: A
A'BB '), 5.456 (1H, d, 16.4Hz,
AB type A part), 5.286 (1H, q, 7.3H
z), 5.222 (1H, d, 16.4 Hz, B part of AB type), 5.200 (1H, q, 7.3 Hz), 5.1
40 (1H, q, 7.3Hz), 4.397 (1H,
q, 6.5 Hz), 1.669 (3H, d, 7.3H)
z), 1.583 (6H, d, 7.3Hz), 1.44
6 (3H, d, 6.5Hz), 0.902 (9H, s,
TBDMS), 0.108 (3H, s, TBDMS),
0.084 (3H, s, TBDMS)

(Synthesis example 7)

Embedded image Compound obtained in Synthesis Example 6 in a 100 ml flask
(7) 1.71 g (2.77 mmol) was dissolved in 5.5 ml of tetrahydrofuran at room temperature to obtain 1.90 ml of acetic acid.
(33.19 mmol), 5.54 ml (5.54 mmol) of a 1 M concentration solution of tetra-n-butylammonium fluoride in tetrahydrofuran was sequentially added. After stirring at room temperature for 24 hours, the mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the crude product obtained by concentration under reduced pressure was recrystallized from ethyl acetate-hexane to give the desired product.
(8) 1.11 g (yield 80%) was obtained. (8) Rf = 0.49 (ethyl acetate: hexane = 1: 1) mp: 88-89 ° C. [α] ²⁰ _D- 93.8 ° (C = 0.93, CH ₃ OH) MS (FAB +, m ^{-NBA) 503 (M (79 Br} ) +1]
⁺ . ^{431 [M (79 Br) -CH} 3 OH (OH) CO]
⁺ . 361 [M ( ⁷⁹ Br) -2xCH ₃ CH (OH) C
O] ^{+ 1} H-NMR (270 MHz, CDCl ₃ ) δ: 7.6
19 to 7.779 (4H, m, aromatic protons: A
A'BB '), 5.469 (1H, d, 16.5Hz,
AB type A part), 5.299 (1H, q, 7.0H
z), 5.228 (1H, d, 16.5 Hz, AB type B part), 5.225 (1H, q, 7.3 Hz), 5.2
09 (1H, q, 7.3 Hz), 4.359 (1H, b
r, q, 7.0 Hz), 2.738 (1H, br.s,
-OH), 1.667 (3H, d, 7.0Hz), 1.
610 (3H, d, 7.3Hz), 1.600 (3H,
7.3 Hz), 1.493 (3H, d, 7.0 Hz)

(Synthesis Example 8)

[Chemical 12] Compound obtained in Synthesis Example 4 in a 100 ml flask
(5) 1.63 g (5.90 mmol) was dissolved in 5.9 ml of methylene chloride, and the system was brought to 0 ° C. Here, 485 mg (3.84 mmol) of diisopropylcarbodiimide
Was added and stirred at 0 ° C. for 10 minutes. Synthesis Example 7 under 0 ° C
1.29 g (2.56 mmol) of the compound (8) obtained in 1. was dissolved in 5.9 ml of methylene chloride and added, then 219 mg (1.79 mmol) of 4-dimethylaminopyridine was added, and the mixture was stirred at 0 ° C. for 30 minutes. , Concentrated under reduced pressure. The mixture was suspended in ethyl acetate, 10% aqueous citric acid solution,
The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. This mixture was suspended in hexane, filtered, and the precipitate was removed to obtain a filtrate. The crude product obtained by concentrating the filtrate under reduced pressure was subjected to silica gel column chromatography (Wako-gel C-30
Purification with 0.130 g of ethyl acetate: hexane = 2: 8) gave 1.80 g of the desired product (9) (yield 92%; from compound (8)). (9) Rf = 0.39 (ethyl acetate: hexane = 1: 3) [α] ²⁰ _D −104.4 ° (C = 0.18, CH ₃ O
H) MS (FAB +, m -NBA) 761 (M (79 Br) +1]
⁺ . ^{783 [(M (79 Br)} + Na] + 1 H-NMR (270MHz, CDCl 3) δ: 7.6
26 to 7.778 (4H, m, aromatic protons: A
A'BB ') 5.467 (1H, d, 16.2Hz, A
B type A part), 5.291 (1H, q, 7.0 Hz),
5.225 (1H, d, 16.2Hz, AB type B
Part), 5.188 (1H, q, 7.3 Hz), 5.18
1 (1H, q, 6.8Hz), 5.172 (1H, q,
6.8 Hz), 5.132 (1H, q, 7.3 Hz),
4.399 (1H, q, 7.0Hz), 1.673 (3
H, d, 7.0 Hz), 1.592 (3H, d, 7.3)
Hz), 1.584 (6H, d, 6.8Hz), 1.5
76 (3H, d, 7.3Hz), 1.538 (3H,
d, 7.0 Hz), 0.904 (9H, s, TBDM
S), 0.110 (3H, s, TBDMS), 0.08
7 (3H, s, TBDMS)

(Synthesis Example 9)

Embedded image Compound obtained in Synthesis Example 8 in a 50 ml flask
(9) 1.30 g (1.71 mmol) was dissolved in 3.4 ml of tetrahydrofuran at room temperature, and 1.17 ml of acetic acid was added.
(20.44 mmol), 3.42 ml (3.42 mmol) of a 1 M solution of tetra-n-butylammonium fluoride in tetrahydrofuran was sequentially added. After stirring at room temperature for 24 hours, the mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate. The crude product obtained by concentration under reduced pressure was subjected to silica gel column chromatography (Wako-g
el C-300. 120 g, ethyl acetate: hexane = 1: 1)
Purification was performed to obtain 1.00 g of the desired product (10) (yield 92%). (10) Rf = 0.49 (ethyl acetate: hexane = 1: 1) [α] ²⁰ _D -116.1 ° (C = 1.1, CH ₃ OH) MS (FAB +, m-NBA) 647 (M ( ⁷⁹ Br) +1]
^{+ 1 H-NMR (270MHz,} CDCl 3) δ: 7.6
16 to 7.776 (4H, m, aromatic protons: A
A'BB ') 5.464 (1H, d, 16.5Hz, A
B type A part), 5.291 (1H, q, 7.0 Hz),
5.226 (1H, d, 16.5Hz, AB type A
Part), 5.215 (1H, q, 7.3 Hz), 5.18
8 (2H, q, 7.0Hz), 5.183 (1H, q,
7.0 Hz), 4.356 (1H, q, 7.0 Hz),
1.671 (3H, d, 7.0Hz), 1.598 (9
H, d, 7.0 Hz), 1.585 (3H, d, 7.3)
Hz), 1.489 (3H, d, 7.0Hz)

(Synthesis example 10)

Embedded image Compound obtained in Synthesis Example 4 in a 50 ml flask
(5) 635 mg (2.30 mmol) was dissolved in 2.3 ml of methylene chloride, and the system was brought to 0 ° C. Here, 218 mg of diisopropylcarbodiimide (1.73 mmo)
1) was added, and the mixture was stirred at 0 ° C for 10 minutes. 744 mg (1.17 mmol) of the compound (10) obtained in Synthesis Example 9 under 0 ° C.
Dissolved in 2.3 ml of methylene chloride and added, followed by 4-
Dimethylaminopyridine 98 mg (0.80 mmol)
Was added, the mixture was stirred at 0 ° C. for 30 minutes, and concentrated under reduced pressure. This mixture was suspended in ethyl acetate and washed with a 10% aqueous solution of citric acid, a saturated aqueous solution of sodium hydrogen carbonate, and a saturated saline solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (Wako-gel C-300. 200 g, ethyl acetate: hexane = 2: 8) to obtain 819 mg of the desired product (11) (yield 77%, compound (10)). More). (11) Rf = 0.28 (ethyl acetate: hexane = 1: 3) [α] ²⁰ _D -121.1 ° (C = 0.36, CH ₃ O
H) MS (FAB +, m -NBA) 905 [M (79 Br) +1]
⁺ . ^{929 [M (79 Br) +} Na] + 1 H-NMR (270MHz, CDCl 3) δ: 7.6
24 to 7.775 (4H, m, aromatic protons: A
A'BB '), 5.461 (1H, d, 16.5Hz,
AB type A part), 5.288 (1H, q, 7.3H
z), 5.228 (1H, d, 16.5 Hz, B part of AB type), 5.131 (1H, q, 7.3 Hz), 5.1
28-5.228 (5H, m), 4.398 (1H,
q, 7.0 Hz), 1.669 (3H, d, 7.0H
z), 1.590 (3H, d, 7.0Hz), 1.58
1 (12H, d, 7.3Hz), 1.574 (3H,
d, 7.0 Hz), 1.446 (3H, d, 7.0H
z), 0.902 (9H, s, TBDMS), 0.10.
9 (3H, s, TBDMS), 0.086 (3H, s,
TBDMS)

[0046]

The L-lactic acid oligomer derivative of the present invention is
It is a novel compound and is a pure compound having no homologues having different degrees of polymerization, that is, having a constant chain length.
These compounds are very effective as standard substances for bioactivity assay for plants and animals, and in the field of biocompatible materials and drug delivery systems that have been actively studied in recent years.

Claims (1)

[Claims] 1. An L-lactic acid oligomer derivative represented by the following general formula (I): Here, R ¹ represents H, an alkyl group, an aryl group, an acyl group or a silyl group, R ² represents H, an alkyl group or an aryl group, provided that R ¹ and R ² are both H None, n is an integer of 0 to 20.