JPH04149151A - Production of 4-bromo-3-hydroxybutyric acid ester derivative - Google Patents

Abstract

PURPOSE:To economically, efficiently and readily obtain the subject compound, especially an optically active substance thereof by reacting an optically active 3,4-dihydroxybutyric acid derivative or a 3-hydroxybutyrolactone derivative with a brominating agent and an alcohol. CONSTITUTION:A compound expressed by formula I or II (R1, R2 and R6 are H or protecting group of alcohol; R3 is H or lower alkyl), especially an optically active (R)-or (S)-isomer thereof is allowed to react with a brominating reagent, preferably a hydrogen bromide reagent, especially a solution of hydrogen bromide in acetic acid, hydrobromic acid/concentrated sulfuric acid or sodium bromide/concentrated sulfuric acid and an alcohol, preferably methanol, ethanol, n-propanol, isopropanol, nbutanol, tert. butanol or isobutanol to efficiently afford the objective compound, expressed by formula III (R4 is H or protecting group of alcohol; R5 is lower alcohol) and useful as an intermediate for medicines, especially an optically active substance corresponding to the aforementioned raw material in high optical purity from the inexpensive raw material.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to 4-bromo-3-hydroxybutyric acid ester derivatives, which are compounds useful as intermediates for synthesizing pharmaceuticals, particularly optically active 4-bromo- The present invention relates to a method for producing a 3-hydroxybutyric acid ester derivative.

[Prior Art] The following method is known as a method for producing an optically active 4-bromo-3-hydroxybutyric acid ester derivative.

(1) A method for producing (S)-4-bromo-3-hydroxybutyric acid ester by asymmetric hydrogenation of 4-bromo-3-ketobutyric acid ester using baker's yeast [Tetrahedron Letters
Vol. 26, No. 1, 101-104 (1985)].

(2) A method for asymmetrically hydrogenating 4-bromo-3-ketobutyric acid ester using a ruthenium-optically active phosphine complex as a catalyst to produce optically active 4-bromo-3-hydroxybutyric acid ester (JP-A-1211551) ).

(3) Ascorbic acid is oxidized with hydrogen peroxide to form a calcium monothreonate salt, which is reacted with an acetic acid solution of hydrogen bromide and alcohol, and further reduced with palladium on carbon to produce (R)-4-bromo - Method for producing 3-hydroxybutyric acid ester [ActaChem, 5cand,
R37341-344, (1983)].

[Problems to be Solved by the Invention] Among the conventional methods, in method (1), the optical purity of the obtained 4-bromo-3-hydroxybutyric acid ester is insufficient, and the absolute configuration is limited to a specific one, Synthesis of enantiomers is difficult. In method (2), the optical purity of the obtained 4-bromo-3-hydroxybutyric acid ester is not yet sufficient, and the reduction must be carried out at high temperature and high pressure. In method (3), 4-bromo-3 with high optical purity
-Hydroxybutyric acid ester can be obtained, but it cannot be said to be an efficient method since it must be further reduced after bromination.

In this way, both methods yield 4-bromo-3
-Hydroxybutyric acid esters have insufficient optical purity and are poor in economic efficiency and operability as an industrial production method, so there are various problems to be solved.

[Means for Solving the Problems] In view of the above circumstances, the present inventors have developed an economical, simple and efficient 4-bromo-3-hydroxybutyric acid ester derivative, particularly an optically active 4-bromo-3-hydroxybutyric acid ester derivative. As a result of intensive studies to establish an industrial production method for hydroxybutyric acid ester derivatives, we found that by reacting inexpensively available optically active 3,4-dihydroxybutyric acid derivatives or 3-hydroxybutyrolactone derivatives with a brominating agent and an alcohol, high optical properties can be obtained. It was discovered that a pure 4-bromo-3-hydroxybutyric acid ester derivative can be efficiently produced, and the present invention was completed.

That is, the gist of the present invention is that formula (I): OR.

In formula 1, R5 and R7 each represent hydrogen or an alcohol protecting group, and R3 represents hydrogen or a lower alkyl group. ] Formula (■): OR.

[In ice, R4 represents a hydrogen or alcohol protecting group, and Rs represents a lower alkyl group. A method for producing a 4-bromo-3-hydroxybutyric acid ester derivative represented by and formula (■).

In formula 1, R6 represents hydrogen or an alcohol protecting group.

4, characterized in that the 3-hydroxybutyrolactone derivative represented by is reacted with a brominating agent and an alcohol.
-Bromo-3-hydroxybutyric acid ester derivative (II)
It consists in the manufacturing method of

In the 3,4-dihydroquinbutyric acid derivative (1) or 3-hydroxybutyrolactone derivative (III) which is the starting material used in the present invention, R1, R2 and Re are each a hydrogen atom or a general hydroxyl group-protecting group, R
3 is a hydrogen atom or a lower alkyl group, especially a carbon number of 1 to 5
lower alkyl groups (eg, methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl or isobutyl). These can be synthesized at low cost from 3-chloro-12propanediol or malic acid [JP-A-2-42050, Chemistry.
Letters (Chemistry Letters)
1 389-1392 (1984,)]. In addition, optically active 3,4-dihydroxybutyric acid derivatives or 3
-Hydroquibutyrolactone derivatives can also be synthesized at low cost from optically active 3-chloride, 2-propanediol or optically active malic acid.

3.4- obtained from 4-dihydroxybutyric acid derivative (1) or 3-hydroxybutyrolactone derivative (I[I)
Bromo-3-hydroxybutyric acid ester derivative (Ill)
, R4 is a hydrogen atom or a hydroxyl group protecting group, R5 is a lower alkyl group, and especially ? Examples include lower alkyl groups having 1 to 5 carbon atoms (eg, methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, or isobutyl).

In this reaction, hydrogen bromide reagent is used as the brominating agent,
For example, hydrogen bromide acetic acid solution, hydrobromic acid/sulfuric acid or sodium bromide/sulfuric acid, etc. can be used in an amount of 1 to 10 equivalents based on the starting material.

4-bromo-3-hydroxybutyrate derivative (n)
In order to obtain a high yield of , it is preferable to use a hydrogen bromide acetic acid solution.

As the alcohol, lower alcohols having 1 to 5 carbon atoms, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, or isobutanol, are used. Equivalent amounts can be used to prepare each corresponding ester (n).

The reaction temperature in the method of the present invention is suitably in the range of 20-100'C. The higher the temperature, the faster the starting material 3,4-dihydroxybutyric acid derivative (1) or 3-hydroxybutyrolactone derivative (III) disappears, but by-products tend to increase, and 4-bromo-3-hydroxybutyric acid ester In order to obtain the derivative (n) in high yield, 20 to 4
It is preferable to carry out the reaction with stirring at 0°C for 2 to 40 hours until the raw materials almost disappear. Isolation and purification can be carried out by distilling off the solvent and unreacted starting materials from the reaction solution under reduced pressure, distributing the residue between ethyl acetate and water, and then distilling off the organic layer under residual pressure. - An oily substance containing a bromo 3-hydroxybutyric acid ester derivative is obtained. For further purification, conventional column chromatography, distillation, etc. may be used.

However, the reaction and isolation/purification operations are not necessarily limited to these methods, and various methods can be used.

Also, optically active 3,4-hydroxybutyric acid derivatives or 3
By using -hydroxybutyrolactone derivatives as starting materials, corresponding optically active 4-bromo-3-hydroxybutyric acid ester derivatives can be synthesized.

[Actions and Effects] According to the present invention, 4-bromo-3-
Hydroxybutyric acid ester derivatives, especially optically active 4
-Bromo-3-hydroxybutyric acid ester derivatives can be produced.

[Examples] Hereinafter, the present invention will be explained in more detail with reference to Examples.
Of course, the present invention is not limited to these.

Example 1 Production of methyl (S)-4-bromo-3-hydroxybutyrate (S)-3,4-dihydroxybutyrate methyl 7°89
Dissolved in 54.6 iρ of 0% hydrogen bromide acetic acid solution and diluted at room temperature for 2
Stirred for 4 hours. Methanol+09ml was added to the resulting solution and stirred for 24 hours. The reaction solution was concentrated under reduced pressure to an orange oil, the residue was partitioned between ethyl acetate and water, the pH of the aqueous layer was adjusted to 7 by adding sodium carbonate solution, and the organic layer was separated. The aqueous layer was further extracted with ethyl acetate.

The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield crude methyl (S)-bromo-3-hydroxybutyrate as an orange oil.

By distilling the obtained crude oil, (S)-4-
14 g of methyl bromo-3-hydroxybutyrate were obtained as an oil (boiling point 79-81'C/I mmHg).

[α colo°= −10,84' (c= L M
eOH)'HNMR (90MHz, CDCl25): δ
=266 (d, 2 H, J, = 6 Hz), 3
．． 31 (s, OH), 3.42 (d, 2 Hj =
5 Hz), 3.71 (s, 3H), 4.12-4.
38 (m, IH).

IR (CCQ4 solution): 3540.2950.1730
．． 1440.1200.1180.1040Cl" Example 2 Production of methyl (S)-4-bromo-3-dihydroxybutyrate (S)-3,4-dihydroxybutyrate 0.59
It was dissolved in 0% hydrogen bromide acetic acid solution (3.5 liters) and stirred at room temperature for 24 hours. Add methanol 12.5xf2 to the resulting solution.
was added and stirred for 24 hours. The reaction solution was concentrated under reduced pressure to give an orange oil, which was again dissolved in 51 ρ of methanol, refluxed for 2 hours, and then concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water, the organic layer was washed with water, then dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude (S).
Methyl-4-bromo-3-hydroxybutyrate was obtained as an orange oil. The resulting crude oil was subjected to silica gel chromatography and hexane:ethyl acetate (=
4:1) to give 0.549 methyl (S)-4-bromo-3-hydroxybutyrate as an oil.

The physical property values were consistent with those of Example 1.

Example 3 Production of methyl (S)-4-bromo-3-hydroxybutyrate 0.5 g of (S)-3-hydroxybutyrolactone was
It was dissolved in a 3.51% hydrogen bromide acetic acid solution and stirred at room temperature for 24 hours. Methanol 12.5311 was added to the resulting solution.
2 was added and stirred for 24 hours. The reaction was concentrated in vacuo to an orange oil, the residue was partitioned between ethyl acetate and water, and sodium carbonate solution was added to reduce the aqueous layer to 7 p.i.
The organic layer was separated, and the aqueous layer was further extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield crude methyl (S)-4-bromo-3-hydroquinobutyrate as an orange oil.

The obtained crude oil was distilled to obtain 0.729% of (S) methyl 4-bromo-3-hydroxybutyrate as an oil (boiling point 79-81'C/1 mmHg).

The physical property values were consistent with those of Example 1.

Example 4 Preparation of methyl (S)-4-bromo-3-hydroxybutyrate (S>3.4-one hydroxybutyric acid 0.59 was dissolved in 3.5 mQ of 30% hydrogen bromide acetic acid solution, and 24 The mixture was stirred for an hour. Methanol 1251 was added to the resulting solution.
Stirred for 24 hours. The reaction solution was concentrated under reduced pressure to an orange oil, the residue was partitioned between ethyl acetate and water, the aqueous layer was adjusted to p)(7) by adding sodium carbonate solution, and the organic layer was separated. The aqueous layer was further extracted with ethyl acetate.The organic layers were combined and dried over anhydrous sodium sulfate.
Concentration under reduced pressure gave crude methyl (S)-4-bromo-3-hydroxybutyrate as an orange oil. By distilling the obtained crude oil, methyl (S)-4-bromo-3-hydroxybutyrate0.6
The physical properties obtained from 569 as an oil were consistent with those in Example 1.

Example 5 Production of methyl (S)-4-bromo-3-hydroxybutyrate 0.5y of methyl (S)-3-(t-butyldimethylsiloxy)-4hydroquinebutyrate was added to a 30% hydrogen bromide acetic acid solution 3
．． Dissolved in 5xC and stirred at room temperature for 24 hours. 12.5 mC of methanol was added to the obtained solution and stirred for 24 hours. The reaction solution was concentrated under reduced pressure to an orange oil, the residue was partitioned between ethyl acetate and water, the pH of the aqueous layer was adjusted to 7 by adding sodium carbonate solution, and the organic layer was separated. The aqueous layer was further extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 1(
S>Methyl 4-bromo-3-hydroxybutyrate was obtained as an orange oil. The resulting crude oil was distilled to give 0.329 methyl (S)-4-bromo-3-hydroxybutyrate as an oil. The physical properties were consistent with those in Example 1.

Reference Example 1 Production of (S)-trimethylmalate 150 g of (S)-malic acid was dissolved in a 3% methanol solution of hydrochloric acid prepared by adding acetyl chloride 50xQ to methanol IQ in advance, and stirred at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure and the residue was distilled to obtain (S)-dimethyl malate 1139 as a colorless oil (boiling point 120-125°/15 mmHg).

[α] et al. 0-91 (c = 2, 2, E to H
)ゝH-NMR (90MH2, CDCl2.): δ=2
．． 68 (d, 2H, J=5Hz), 3.60 (s, 3H
), 3.69 (s, 3H), 3.78 (s, I H, O
H), 4.37 (tIH, J=5Hz).

Reference Example 2 (S>3.4-Production of methyl dihydroquine butyrate (S)-
19.4 g of trimethyl malate was dissolved in 250xQ of anhydrous tetrahydrofuran (THF), and porane methyl sulfide! 2.2×Q was added and the mixture was stirred at 20° C. for 30 minutes. Next, sodium borohydride (NaBH*)0
．． After adding 2g of anhydrous methanol and stirring for another 30 minutes,
Added 7xC. By distilling off the solvent etc. under reduced pressure, the crude (
Methyl S)-3,4-dihydroquine butyrate was obtained as an oil. The resulting crude oil was purified by gel chromatography and eluted with ethyl acetate (
14 g of methyl S)-3,4-dihydroquine butyrate were obtained as an oil.

[α]′D. =-25,0°(c=3,12,M
eOH)'HNMR (90MHz, CDCQs): δ-
=2.53 (d, 2H, J=6Hz), 3.0-3.9
(m, 4H), 3.7 (g, 3H), 3.97-4.2
7 (++I, IH).

Reference Example 3 Production of (S)-0-acetylmalic acid anhydride 13.49% of (S)-malic acid was dissolved in acetyl chloride 50ii7 and stirred at 40°C for 2 hours. By distilling off excess acetyl chloride and produced acetic acid under reduced pressure (S)
16.179 of -0-acetylmalic anhydride was obtained as a colorless oil.

[α] is also 0 = -26,0° (c-5,11, CHCQs
)'HNMR (90MHz, CDCf2s): δ-2,
22(s, 3H), 3.06(dd,]H,J=1
9.7Hz), 3.41 (dd, IH, J=19.9H
z), 5, 6 (dd, IH, J=7.9Hz).

Reference Example 4 Production of (S)-0-acetylmalic acid-1 methyl ester (S)-0-acetylmalic anhydride (12.641/) was dissolved in methanol (160IIIθ) and stirred at room temperature for 12 hours. Crude (S) is obtained by distilling off methanol under reduced pressure.
-0-acetylmalic acid-1 methyl ester is, ss
g was obtained as a colorless oil.

[α]6°=-27.9°(c=9,25,Me
OH)'HNMR (90MHz, CDCf2s): δ=
2.1 (s, 3H), 2.9 (d, 2H, J=6Hz)
, 3.7 (s.

3H), 5.45 (t, IH, J=6Hz).

Reference Example 5 Production of (S)-3-hydroxybutyrolactone Sodium borohydride (1069%) was mixed with t-butanol (142%). E+
+Q and reflux, and (S)-〇-acetylmalic acid-1 methyl ester 13゜39 [-butanol 5
67 Mρ and a solution dissolved in methanol 113 rice grains
It dripped over time. Thereafter, the mixture was further refluxed for 2 hours.

Pre-mix acetyl chloride 255 to methanol 170+
In addition to Q, a methanol solution of hydrochloric acid prepared was slowly added to the reaction solution to make it acidic, and then the solvent and the like were distilled off.

Ethyl acetate was added to the residue and filtered, and the filtrate was concentrated under reduced pressure to obtain crude (S)-3-hydroxybutyrolactone 8.
．． 69 was obtained as an oil. The obtained crude oil was purified by silica gel chromatography and eluted with hexane and ethyl acetate (=1.1) to obtain (S)-3.
-Hydroxybutyrolactone 5.19 was obtained as an oil.

mα]o0-81' (c=1,9,7,E
to H)H-NMR (90MHz, CDCl25):
δ-2,22(m, IH), 2.78(ddiH,
J=18Hz, J=6Hz), 4. ．． 2-4.7 (m,
4H).

Reference Example 6 Production of (S)-3-Hydroxybutyrolactone After dissolving 6.189 of sodium cyanide (NaCN) and 8.599 of sodium hydroxide in 100x (1) of water, R-3- Chlor-12-propanediol 1
1.1g of water 25j+Q solution was slowly added dropwise to 80°C.
The mixture was stirred for 15 hours. After the reaction, the reaction solution was cooled to 0°C and adjusted to pH 1 or less with 6N hydrochloric acid, and volatiles were distilled off.
Methanol was added and the precipitated solid was filtered off. The residue obtained by distilling off methanol from the filtrate was subjected to silica gel chromatography and hexane:acetone (=
(S)-3-
Hydroxybutyrolactone 4.5f! was obtained as an oil.

The physical property values were the same as Reference Example 5.

Reference Example 7 Production of (S)-3,4-dihydroxybutyric acid NaCN12
．． After dissolving 36 g of NaOH and 17.17 g of water in 200 yt (l) of water, a solution of 22.2 g of R,-3-chloro-1°2-propanediol in 50112 water was slowly added dropwise at 0°C, and the mixture was stirred at 80°C for 15 hours. .After the reaction, reduce the reaction solution to 0.
The pH was adjusted to 2.5 with 6N hydrochloric acid while cooling to °C, and after distilling off volatile substances, methanol was added and the precipitated solid was filtered. The residue obtained by distilling off methanol from the filtrate was purified by silica gel chromatography (hexane, acetone = 1:1) to obtain 15.8 g of (S)-3,4-dihydroxybutyric acid as an oil.

[α] is also 0=-27,9° (c=0,96, Me
OH)'HNMR(90MH2, CDC(!s, cD3
0D): δ-2,47-2,63(m,2H), 3.6
(d, 2H.

J=5Hz), 3.97-4.3 (m, IH), 4.7
75.32 (m, 3H).

T R (neat): 3300.2900, 1.710
．． 1390, l 180, l O30cm-'Reference Example 8 Production of dimethyl (S)-2-(t-butyldimethylsiloxy)succinate 7 g of dimethyl L-malate and 35 g of dimethylformamide
Add 61 g of imidazole to a solution consisting of xQ at room temperature,
After stirring for 5 minutes, 16.1 g of a 50% methylene chloride solution of t-butyldimethylsilyl chloride was added over 10 minutes, and the mixture was stirred at room temperature for 15 hours. Add 100ffC of water to the reaction solution.
was added and stirred for 10 minutes, then diluted with methylene chloride 1001
After extraction and drying with sodium sulfate, the solvent and by-product t
-Butyldimethylsilanol was distilled off under reduced pressure. The obtained residue was subjected to Norica gel column chromatography (hexane.

(S)2-(
t-Butyldimethylsiloxy) dimethyl succinate 117
I got g.

H-NMR (CDC(!3): δ-0,08(s, 3H
), 0.17 (s, 3H), 0.88 (s, 9H), 2
．． 67-2.87 (m, 2H), 3.66 (s, 3H)
, 3.73 (s.

3H), 4.55-7.67 (mi, H).

IR(neat): 2975.1750.1445
, l 180.840c111-' Reference Example 9 Production of methyl (S)-1(t-butyldimethylsiloxy)-4hydroquine butyrate (S)-2"-(t-butyldimethylsiloxy)dimethyl succinate 0.83 g Add 22 g of NaB H40 to a solution consisting of 8,3 yQ methanol at -10°C,
The mixture was further stirred at 10°C for 2.5 hours. Add 5% to the reaction solution at 0°C.
After adding 30 ml of NH, CI aqueous solution, 6N hydrochloric acid was added to neutralize. After extracting twice with methylene chloride 50xQ, drying with sodium sulfate and distilling off the solvent under reduced pressure, the resulting residue was purified by column chromatography on linica gel (hexane/acetone - 5:1) to obtain liquid (S )−
058 g of methyl 3-(t-butyldimethylsiloxy)-4-hydroxybutyrate was obtained.

H-NMR (CDCJL) δ-0,1 (s, 3H)
,0,i,2(s,3H),2.0-2.27(m,I
H), 2°6 (d, 2H, J = 6Hz), 3.5-3
．． 82 (m, 2H), 3.72 (s, 3H), 4.1-
4.45 (m, 1.H).

IR(neat):3460.2950.1740.
1260, 1 l 10, 840, 780 cm-' [1
几0=-38,95°(c=2,11, MeOH
) Patent applicant Kanebuchi Chemical Industry Co., Ltd.

Claims (1)

[Claims] 1. Formula (I): ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R_1 and R_2 are hydrogen or an alcohol protecting group, respectively, and R_3 is hydrogen or a lower alkyl group. represents. ] The 3,4-dihydroxybutyric acid derivative represented by the formula (
II): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) [In the diagram, R_4 is a hydrogen or alcohol protecting group, R_
5 represents a lower alkyl group. ] A method for producing a 4-bromo-3-hydroxybutyric acid ester derivative. 2. Optically active (R) or (S)-3 as a starting material
, 4-dihydroxybutyric acid derivative to synthesize a corresponding optically active (R) or (S)-4-bromo-3-hydroxybutyric acid ester derivative. 3. The production method according to claim 1 or 2, wherein a hydrogen bromide reagent is used as the brominating agent. 4. The production method according to claim 3, wherein a hydrogen bromide acetic acid solution, hydrobromic acid/concentrated sulfuric acid, or sodium bromide/concentrated sulfuric acid is used as the hydrogen bromide reagent. 5. The production method according to any one of claims 1 to 4, wherein the alcohol is methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, or isobutanol. 6. The production according to any one of claims 1 to 5, wherein methyl (S)-4-bromo-hydroxybutyrate is synthesized by reacting methyl (S)-3,4-dihydroxybutyrate with a hydrogen bromide acetic acid solution and methanol. Law. 7. Formula (III): ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (III) [In the formula, R_6 represents hydrogen or an alcohol protecting group. ], characterized by reacting a 3-hydroxybutyrolactone derivative represented by the following with a brominating agent and an alcohol,
Formula (II): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) [In the formula, R_4 is a hydrogen or alcohol protecting group, R_
5 represents a lower alkyl group. ] A method for producing a 4-bromo-3-hydroxybutyric acid ester derivative. 8. Optically active (R) or (S)-3 as a starting material
8. The production method according to claim 7, wherein the corresponding optically active (R) or (S)-4-bromo-3-hydroxybutyric acid ester derivative is synthesized using the -hydroxybutyrolactone derivative. 9. The production method according to claim 7 or 8, wherein a hydrogen bromide reagent is used as the brominating agent. 10. The production method according to claim 9, wherein a hydrogen bromide acetic acid solution, hydrobromic acid/concentrated sulfuric acid, or sodium bromide/concentrated sulfuric acid is used as the hydrogen bromide reagent. 11. The production method according to any one of claims 7 to 10, wherein the alcohol is methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, or isobutanol. 12. Claims 7 to 1, wherein methyl (S)-4-bromo-3-hydroxybutyrate is synthesized by reacting (S)-3-hydroxybutyrolactone with a hydrogen bromide acetic acid solution and methanol.
1. The manufacturing method according to any one of 1.