JPS6115847A - Nitration process - Google Patents

Abstract

PURPOSE:To produce a nitric acid ester, in high yield and purity, economically in an industrial scale, easily under mild condition, using a regenerable reagent, by reacting a sulfonic acid ester with an organic quaternary ammonium nitrate. CONSTITUTION:The objective compound of formula III can be produced by reacting (A) the sulfonic acid ester of formula II (R'SO2 is sulfonic acid residue) obtained by the conventional sulfonation process of an alcohol of formula I (R is organic residue) with (B) the organic quaternary ammonium nitrate of formula IV(Q<+> is organic quaternary ammonium residue), e.g. a quaternary alkyl (or substituted alkyl) ammonium nitrate or a nitrate of a strongly basic anion exchange resin having quaternary ammonium as an exchangeable group. The process can be applied to a compound which is difficult to be nitrated by conventional methods. When the process is applied to an optically active compound, a nitrate having inverted absolute configuration is prepared without causing racemization.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for nitric acid esterification of oxy compounds.

Conventionally, nitric esters have been produced by (1) directly converting alcohols into nitric esters using concentrated nitric acid, a nitric acid-sulfuric acid mixture, acetyl nitrate, benzoyl nitrate, etc. or (2) converting alcohols into nitric esters using silver nitrate. It is produced by reacting with mercury nitrate, etc. to form a nitrate ester.

However, in method 1), it is difficult to handle the nitric acid esterification reagent and set the reaction conditions, and industrially, equipment to avoid the risk of explosion is required. When applied to aromatic compounds, aromatic nucleus nitration proceeds simultaneously as a side reaction, resulting in poor yield and purity of the desired nitric acid ester, and especially when it comes to aromatic compounds with electron-donating substituents, the desired product cannot be obtained. There are drawbacks. In addition, method (2) has problems such as expensive reagents and the need for recovery treatment of silver and mercury produced after the reaction, making it unsuitable for industrial production.

The present inventors focused on the industrial usefulness of various nitrate ester compounds, and as a result of repeated studies to develop a simple and efficient method for synthesizing these compounds, the present inventors found that they can be processed under mild conditions and can be easily synthesized. , high yield using reusable reagents,
We have discovered a method for producing nitrate esters with high purity.

The present invention is a nitrate esterification method characterized by reacting a sulfonate ester with an organic quaternary ammonium nitrate.

According to the method of the present invention, nitric acid esters can be produced industrially advantageously.

The sulfonic acid esters used in the present invention can be obtained by converting an oxy compound such as an alcohol into a sulfonic acid ester using a conventional method.

The reaction of the method of the present invention is shown by the following formula.

acid (in the formula, R is an organic residue, R'=SO2- is a sulfo residue,
■ Q represents an organic quaternary ammonium residue. ) As a reaction similar to the method of the present invention, J, Am.

There is a method described in a paper published in Chema 3o'c, Vol. 87, pp. 476o-4781, 1965. According to this method, an organic halogen compound and a quaternary ammonium nitrate are reacted, but since it is a reversible reaction, the reaction is not completed.

Therefore, even if this method is applied to the synthesis of nitric acid esters, the yield is poor and separation operations are required, making it unsuitable for industrial production.

The reaction between the sulfonic acid ester and the quaternary ammonium nitrate in the present invention is an irreversible reaction due to the strong affinity between the leaving group sulfonic acid and the quaternary salt, and the reaction progresses in proportion to the passage of time. Nitric acid esters can be produced almost quantitatively.

Examples of alcohols that can be nitrated by the method of the present invention include aliphatic, aromatic, or heterocyclic groups such as pyridine rings, indole rings, quinoline rings, and benzobylane rings.
It may be a -class, secondary or tertiary alcohol. These alcohols may further have substituents such as alkyl groups, halogen atoms, hydroxyl groups, alkoxy groups, acyl groups, and amine groups.

In carrying out the present invention, the alcohol of formula I is first converted into a sulfonic acid ester of formula (2) by a conventional method. As the sulfonating reagent, active derivatives such as halides and acid anhydrides of alkylsulfonic acids such as methanesulfonic acid and ethanesulfonic acid, and aromatic sulfonic acids such as benzenesulfonic acid, toluenesulfonic acid and nitrobenzenesulfonic acid are used.

The sulfonic acid ester (It) is then reacted with an organic quaternary ammonium nitrate to obtain a nitrate ester.

Examples of quaternary ammonium nitrates include (1) quaternary alkyl (substituted alkyl) ammonium nitrates such as tetramethylammonium nitrate, tetraethylammonium nitrate, tetrabutylammonium nitrate, benzyltributylammonium nitrate, or (2) quaternary ammonium with an exchange group. A nitrate of a strongly basic anion exchange resin having as

As a strong basic anion exchange resin having quaternary ammonium as an exchange group, the strongest basic anion exchange MR type (
Macroreticular type) resins for non-aqueous solvents are particularly preferred, such as Amberlis) A-26 (manufactured by Rohm and Haas), Diaion HPA25 (manufactured by Mitsubishi Chemical Industries, Ltd.), or Anno+A for -membrane solvents. −.

900, IRA-904, RA-4oo (manufactured by Rohm and Haas), etc. are used.

The quaternary alkyl ammonium nitrate (1) is produced, for example, by the following method. A strongly acidic ion exchange resin (H type) is reacted with a tetraalkylammonium halide, and then with a nitric acid aqueous solution. Next, the nitric acid aqueous effluent is extracted with dichloromethane, washed, dried, and then dichloromethane is distilled off to obtain quaternary alkyl ammonium nitrate.

The nitrate of the strongly basic anion exchange resin (2) can be produced, for example, by the following method. Amber List A-26 (C
Type 1) was brought into contact with an aqueous sodium hydroxide solution to undergo ion exchange to the OH type, and then brought into contact with an aqueous nitric acid solution.
Wash and dry Amberlis) A-26 nitrate (No.
Type 3) can be manufactured.

The method of the present invention can be applied to various organic compounds, such as alkyl groups,
It can be applied to aromatic compounds having alkoxy groups, compounds having hydroxyl groups (alcoholic, phenolic), and imide groups. Further, even in the case of secondary sulfonic acid ester derivatives, the reaction can proceed without being accompanied by an elimination reaction. Compounds that are susceptible to oxidation, such as 1,4-dihydropyridine derivatives, are difficult to convert into nitrate esters using conventional methods, but according to the method of the present invention, these compounds can be converted into nitrate esters. Furthermore, since this reaction proceeds under neutral conditions, it can also be applied to acidic or basic unstable compounds.

Furthermore, when applied to optically active compounds, it is possible to produce nitrate esters with inverted absolute coordination without racemization. That is, when an R-form (8-form) alcohol is used as a raw material, an 8-form (R-form) nitric acid ester can be obtained. Therefore, by reducing the obtained optically active nitric ester, it is also possible to produce an optically active alcohol with an inverted absolute configuration from the raw alcohol.

Reference Example 1 Preparation of quaternary alkyl ammonium nitrate 75 g of tetra-n-butylammonium bromide and 500 g of water were added to a column.
ml solution.

Furthermore, after passing 300 ml of water, 1.51 mL of a 6N-nitric acid aqueous solution was passed through. The nitric acid effluent is extracted twice with 700 ml and 300 ml of dichloromethane, and the dichloromethane layer is washed with saturated saline and dried. Dichloromethane was distilled off to obtain a white solid, which was recrystallized from ethyl acetate-ether to give tetra-n-butylammonium nitrate 53 as colorless prismatic crystals with a melting point of 121°C.
．． 2.9 (yield 75.1%) is obtained.

After the obtained tetraalkylammonium nitrate is used in the reaction of the present invention, it becomes a tetraalkylammonium sulfonate, which is again converted into the above-mentioned Diaion 5KIB (
After adsorption to H type), ion exchange using nitric acid,
Can be used for playback.

Reference Example 2 Preparation of Strongly Basic Anion Exchange Resin Type Quaternary Ammonium Nitrate 500 g of Amberlyst A-26 (C1 type) (manufactured by Rohm and Haas) was packed into a column, washed with water and methanol, and then .5N-sodium hydroxide aqueous solution 31 is passed through it to convert it into an OH form.

Next, after washing with 3.5 liters of ion-exchanged water, an IN-nitric acid aqueous solution 31 is passed through to convert it into a nitrate type (oNo2 type). Wash with deionized water until the pH of the wash effluent is 7. After sequentially washing with ethanol 2A and acetone 11 to remove water, the product was heated and dried, followed by vacuum drying to obtain 211 g of Amberlystom-26 nitrate (ONO□ type).

After the obtained Amberlis (A-mo□ type) is used in the reaction of the present invention, it becomes a sulfonate (O802R type). This can be easily converted into the 0N02 type by converting it into an OH type using sodium hydroxide or the like and then ion-exchanging it again using nitric acid, and can be reused.

In addition, it can be converted into 10NO,. type by directly passing through a sodium nitrate NaNO3 aqueous solution.

Example 1 (1) 2-(t-butoxycarbonylamine/)-2',
6'-dimethyl-4'-(2-hydroxyethoxy)propionanilide 19.4. ! 9.) Liethylamine 9
．． 2 ml and 4-dimethylaminopyridine 1,34
,! Dissolve i' in 200 ml of tetrahydrofuran,
Gradually add 4.7 ml of ice water chloride and methanesulfonic acid chloride. After completion of the dropwise addition, the mixture was stirred at room temperature for 2 hours, the precipitate was removed, the solvent was distilled off, and the resulting residue was dissolved in ethyl acetate. After sequentially washing with dilute hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated brine, the solvent was distilled off and the resulting residue was recrystallized from ethyl acetate to give 2-(t-butoxycarbonyl) as colorless crystals with a melting point of 114-116°C. amino) -2
',6'-dimethyl-4'-(2-methane (2) 1.50 g of the obtained methanesulfonyl compound and 2.109 g of tetra-n-butylammonium nitrate were added to 1.8 g of dioxane.
ml and stirred for 4 hours at a bath temperature of 90'C. The mixture is then dissolved in benzene, washed with water, dried, and the benzene is distilled off. The residue is subjected to silica gel column chromatography and eluted with benzene to give a colorless oil. When this is recrystallized from ethyl acetate-n-hexane, 2-(t-butoxycarbonylamino) z/,
6'-dimethyl-4'-(2-nitroxyethoxy)
1.34 g (yield 96.7%) of propionanilide is obtained.

Br IR value"'maxm-' 1682.1660.1665.1277.847NM
R value: δCDC13 1,42 (9H,s, -C(CH3)3)1-42
(6HS, d 1J-7Hz1/CH""Hs)4,
10~4.24 (2H, m, -0CH20H2-)
4.70~4.84 (2Hlm, -CH,,0NO
2) 5.35 (H, d, J=7 Hzl-NHCO
O-)6.50 (2H,s, aromatic ring H) HRMS value: 697.1849 (M) Examples 2-1
5 The following compounds can be produced in the same manner as in Example 1. The reaction conditions, physical properties of the target product, etc. in steps (1) and (2) are as follows.

Example 2 (1) Production of 3-phenylpropyl methanesulfonate Starting material: 3-phenylpropatool Reaction conditions: methanesulfonic acid chloride/pyridine Yield 95.0%, colorless oil.

NMR value: δCCl4 1,84~2.20 (2H,m, -CJ(,,CH
2CH2-)2.85 (3H,s, -0302CH
,)4.15 (2H,t,' J=7 Hz, -C
H2O802-) 7.00-7.40 (5H, m1 aromatic ring H) (213-Phenylpropyl nitrate production Starting material = sulfonic acid ester of (1) Reaction conditions: Tetra-n-butylammonium nitrate, toluene, 90
°C, 6 hours Yield 96.2%, colorless oil.

1628.1278.860 (-ONO2) NMR value: δCDCl 3 2.00 (2H,q, J=8 Hz, -CH,
, CH2CH2-)4.38 (2H, tl, T=a
Hz, -CH20NO,,)7.0D~7.40(5
H1m1 aromatic ring H) Example 6 (1) Production of 2-phenoxyethyl p ~ toluenesulfonate Starting material = 2-phenoxyethanol Reaction conditions: toluenesulfonic acid chloride/triniblamine, tetrahydrofuran (THF), 4-dimethylamino Pyridine yield 95.2%, colorless plate crystals, melting point 74
~75℃.

NMR value: δCDC13 2,44 ('5 Hls, -C equivalent) 4.04-4.26 (2n, ml-OCH2CH2-
)4.28~4.48 (2H,, m, -CH2CH
2-)6.64-7.48 (7Hlm, aromatic ring H)7
．． 68-7.90 (2H, d, J = 10Hz, aromatic ring H) (2) Production of 2-phenoxyethyl nitrate Starting material: Sulfonic acid ester reaction conditions of (1): Tetraethylammonium/nitrate, 80°C, 6 hours yield 95.5%, colorless oil.

1667.1279.850 (-ONO,,)NMR
Value: δCDC13 4.66~4.88 (2H, m, -CH20NO2
)6.72-7.04 (3H, m, aromatic ring H)7.1
．． 2-7.43 (2H, m, aromatic ring H) HRMS value:
183.0567 (M+) Example 4 Using 2-phenylethyl-p-toluenesulfonate obtained in Example 6 (1), 2-
Phenylethyl nitrate was produced (yield 97.6
%).

Reaction conditions: benzyltributylammonium/nitrate,
Acetonitrile, 80°C, 16 hours Example 5 (1) Starting material for production of 2-(4-chlorophenyl)ethylbenzenesulfonate'! :2-(4-chlorophenyl)ethanol Reaction conditions: Benzene sulfonic acid chloride/pyridine yield 92.1%, colorless oil NMR value: δCDC13 4, 18 (2H, t, J=7 Hz, -CH2OS
O2-) 6.88-7.24 (4H, d,, d,
J = 10Hz, aromatic ring H) 7, 66 ~ 7.80 (5H
, m, aromatic ring H) (2) Production of 2-(4-chlorophenyl)ethyl nitrate Starting material: Sulfonic acid ester of (1) Reaction conditions: Tetra-m-butylammonium nitrate, toluene, 80°C
, 40 minutes yield 97.5%, colorless clear autumn product.

1635.1278.848 (-ONO2) NMR value: δCDC13 2,94 (2Hlt, J=7 Hz, C1-(1
)-CH2-)4.56 (2H,t, J=7 Hz
, -CH20NO2)7.05 (2H,d, J
=8Hz, aromatic ring H)7.22 (2Hld, J=8
Hz, aromatic ring H) HFtMS value: 201.0169
(M″-) Example 6 (112-(4-chlorophenyl)ethyl-〇-nitrobenzenesulfonate production Starting material: 2-(4-chlorophenyl)ethanol Reaction conditions 20-nitrobenzenesulfonic acid polyloride/triethylamine , THF yield 80.5%, pale yellow clear autumn product.

NMR value: δCDC13 4,42 (2H, t, J=7 Hz, -CH2O8
0,,-)6.96-7.62 (4H,m, aromatic ring H
)7,56+-7,95(4H,m, aromatic ring H)(21
Production of 2-(4-chlorophenyl)ethyl nitrate Starting materials: Sulfonic acid ester of (1) Reaction conditions: Tetra-n-butylammonium nitrate, dioxane, 4
The yield at 0'C16 hours was 85.6%, and the IR value, NMR value, and MS value were the same as in Example 5(2).

Example 7 (1) Production of 1-methyl-2-phenoxyethyl-p-toluenesulfonate Starting material: 1-methyl-2-phenoxyethanol Reaction conditions: Toluenesulfonic acid chloride/pyridine Yield 92.0%, colorless needles Crystal, melting point 92-96CO NMR value: δCDC13 6,60-7. CJ 8 (5H, m, aromatic ring H) 7,
10-7.42 (4H, m, aromatic ring H) 7,80 (
2H, d, J = 8 Hz 1 aromatic ring H) (2) Production of 1-methyl-2-phenoxyethyl nitrate Starting material: Sulfonic acid ester of (1) Reaction conditions: Tetra-n-butylammonium nitrate, toluene, 90
'C16 hour yield 97.7%, colorless clear fall product.

1660.1278.850 (ONO,,) NMR value: δCDC13 5,60-5.60 (H, m1CHCH3)6,80
~7.10 (6H, m1 aromatic ring H)7.20~7.4
4 (2H, m1 aromatic ring H) Example 8 (1) 2-(4-methoxyphenoxy)ethyl-〇-nitrobenzene sulfonate Starting material: 2-(4-methoxyphenoxy)ethanol Reaction conditions 20-nitrobenzene Sulfonic acid chloride/triethylamine, THF yield 85.0%, pale yellow oil.

NMR value: δCDC1°3.72 (3H,s, CH30-)4.48-4.
68 (2H, ml-CH20SO2-)6.70(4
H1s, aromatic ring H) 7, 60-7.85 (3H, m1 aromatic ring H) 8.00
~8.20 (H, rn, aromatic ring H) (2) 2-(4-
Production of methoxyphenoxy)ethyl nitrate Starting material: Sulfonic acid ester of (1) Reaction conditions: Tetra-n-butylammonium/nitrate, acetonitrile, 50°C, 5 hours Yield: 98.1%, colorless clear product.

1668.1279.84 B (-ONO2)NMR
Value: δCDC13 6,72 (3H, s, CH30-') 4.08-4.
24 (2H, m, CH20b) 4.68-4.83
(2H, m, -CH3CH2(,0NO2)6.80
(4H,s, aromatic ring H) HRMS value: 213.0642 (M+) Example 9 (Production of 112-(3-methylphenoxy)ethyl methanesulfonate Starting material: 2-(6-methylphenoxy)ethanol Reaction conditions: Methanesulfonic acid chloride/pyridine yield 91.0%, colorless clear product.

NMR value: δCDC13 3,04 (3H, 5l-O8O2CH3) 4.48-4
．． 68 (2H,m, -CH,,0802-)6.6
0-6.88 (3H, m1 aromatic ring H) 7.04-7.
24 Production of (H, m1 aromatic ring H) (212-(3-methylphenoxy)ethyl nylate) Starting material: Sulfonic acid ester of (1) Reaction conditions: Tetramethylammonium/nitrate, dimethyl sulfoxide, 90°C, 23 Time yield 52.9%, pale yellow oil.

1669.1278.845 (-ONO2) NMR value:
δcDc13 2, 30 (3H, s, C!l!, -) 4, 12~4
．． 32 (2H,m, -CH,,CH20NO2)4
．． 72~4.90 (2H, m, -CH,0NO2)
6.60-6.90 (3H, m, aromatic ring H) 7,05
~7.30 (H, m, aromatic ring H) HRMS value: 19Z
o686 (M+) Example 10 (1) Production of 2-octylbenzenesulfonate Starting material: 2-octatool reaction conditions: benzenesulfonic acid chloride/pyridine yield 91.1%, colorless clear product.

NMR value: δCDC'13 0.76-1.00 (3Hlm, CH3CH2-)
1.00~1.75 (15H, m, -(CH2)5
-1. 'CHCH3) 7.84~8.03 (2H1b
r, d, J = 8 Hz, aromatic ring H) (2) Production of 2-octylnylate Starting material: Sulfonic acid ester reaction conditions of (1): Tetra-n-butylammonium nitrate, toluene, 90%
℃, 4 hours Yield 95.6%, pale yellow oil.

1621.1277.874 (-〇NO2) NMR value: δCDC1゜0.76-1.04 (5H, m, CH3CH2-)
4.86~5.18 (H, m, □'CHCH3)/
Example 11 (1) Production of 3-(3-pyridijL/)propyl methanesulfonate Starting material: 6-pyridinepropanol Reaction conditions: Toluenesulfonic anhydride/THF Yield 9
5.2%, pale yellow oil.

NMR value: δCDC13 1,96-2.24 (2H,m, -aH2an,a
H,,-)2.98 (5H,s, -CH3) 4.26(2H,t, J=6 Hz, -CH2OS
O2-)7,1(]-7,32(H,m, pyridine ring 5
position H) 7,42-7.58 (H,m, pyridine ring 4th position H)8.36-8.48 (2H,m, pyridine ring 2
．． 6-position H) (2) Production of 5-(3-pyridyl)propyl nitrate Starting material: Sulfonic acid ester of (1) Reaction conditions: Tetra-n-butylammonium nitrate, toluene, 90°C
, 3 hours yield 698%, colorless clear fall product.

NMR value: δCDC13 1,88~2.24 (2H,m, -CH2CH,,
CH2−)2.76 (2H,t, J =7 Hz,
-CH2CH2CH20NO2)4.44(2H,t
, J=7Hz, -CH20NO2)7, 14~7.32
(H, ml pyridine ring 5th position H) 7.40-7.56
(H, m, H at position 4 of pyridine ring) 8.62-8.52
(Hlm, H at positions 2 and 6 of pyridine ring) HRMS value: 22
5.0629 (M+) Example 12 m 3-Methanesulfonyloxy-8-methoxy-3
, 4-dihydro-2H-l-benzopyran Starting material = 6-hydroxy-8-methoxy-3,4-dihydro-2H-l-benzopyran (JP-A-59-296
Compound described in Publication No. 81) Reaction conditions: methanesulfonic acid chloride/pyridine yield 890%, colorless needle crystals, melting point 104-105°C.

NMR value: δCDC13 2,90-3.40 (2H, m, C, -2H) g,
o 3(6H,S,-080,,CH3)5.136
(3H1s, -0CH,)4.12~4.54 (2
H1m1 C2-2H) 5, 10~5.30 (Hlm
, c3-H)6,58-6.96 (5H, m, aromatic ring H) (2) 8-methoxy-6-nithoxy5.4-
Production of dihydro-2H-l-benzopyran Starting material: Sulfonic acid ester of (1) Reaction conditions: Tetra-n-butylammonium nitrate, toluene, 90°C
, 14.5 hours yield 799%, colorless needles, melting point 79~
80℃.

1616.1280.875 (-ON'02)NMR
Value: δCDC13 2.84-3.44 (2H, m, C, -2H) 5.8
5 (3H, 5l-OCH,) 4.16-4.56 (2H, m1C,, 2H) 5, 3
5-5.53 (H, m, O3-H)6.56-6
．． 96 (3Hlm, aromatic ring H) HRMS value: 225
．． 0629 (M+) Example 16 (1) Production of 2-(4-ethoxycarbonyloxyphenoxy)ether methanesulfonate Starting material: 2-
(p-hydroxyphenoxy)ethanol reaction conditions: chloroethyl carbonate/triethylamine,
THF methanesulfonic acid chloride/triethylamine yield 97.7%, colorless needles, melting point 75-76°C.

NMR value: δCDC13 1, 40 (3H, t, J=7 Hz, -0CH2C
H3) 3.05 (3H, 5l-O8O2CH3)4,
32 (2, Hlq, J = 7 Hz, 0C
H2CH3)4,50~4.65 (2H,m, -C
H2O802-)6.90 (2H, d, J = 10
Hz, aromatic ring H)7,15 (2H,d, J=10H
z, aromatic ring H) (2) Production of 2-(4-ethoxycarbonyloxyphenoxy)ethyl nitrate Starting material: Sulfonic acid ester of (1) Reaction conditions: Tetra-herbal ammonium nitrate, dioxane, 90%
°C, 4 hours yield 96.5%, colorless needles, melting point 45.5-46 °C.

t759 (c=o), 1626.1286' (0NO
2) NMR value: δCDC13 1, N', 8 (3H, t, J=7 Hzl-OCH
2CH3) 4.28 (2H,,q, J-7Hz
, 0CR2CH3)4.72~4.85 (2Hl
m, -CH2CH20NO2)6.80 (2H1d
1J=10Hz, aromatic ring H)7.05 (2H1d,
J=10Hz, aromatic ring H) HFtMS value: 271.0
693 (M+) Example 14 (1) 2,6-dimetheru-4-(6-nitrophenyl)
Preparation of enesulfonyloxypropyl) ester Starting material = 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydrobiricin-3,5-dicarboxylic acid-6-ethyl ester-3-(6- hydroxypropyl) ester reaction conditions: toluenesulfonyl chloride/pyridine yield 86.1%, pale yellow oil.

NMR value: δCDCl.

1.24 (6H,,t, J=7Hz, -0CH2
CH3) Sardine? 1,95 (2J-7Hz, CH2CH2CH"
)2.65 (6H, s12, 6th position-C'H,)3.9
2 to 4.24 (6H, m, -0CH2CH3, -C
H2CH2C per 7) 5.01 (Hls, 4th position H) 6.00 (H, br, s, -Ndan-) 7.25~
8.12 (8H, aromatic ring H) (2) 2,6-dimethe-4-(3-nitrophenyl)-1,4-dihydropyridine-6,5-dicarbo starting material: Sulfonic acid ester reaction conditions of (1) : Tetra-n-butylammonium nitrate, toluene, 80°C, 4 hours, yield 88.0%, pale yellow prismatic crystals, melting point 164-16
5°c.

3362 (-NH), 1698 (-COOC,,H,
), 1629.1275 (-ONO2) NMR value; δCDCl3 1.24 (6H, t, J=7 Hz, -0CH2
CH3)2,02 (2H,q, J =7 Hzl-
CH2CH2CH2-)2.35. ;2.38 (6H
1s, 2.6th position -CH5)4,12 (2H,q1J near Hz, -0CH2CH3)4,16 (2H,t
, J=7 H2, -0CH, CH2CH20NO2)
4,36 (2H,t, J =7 Hz, -ocH
2aH,,aH2oNo,,)5.08 (H,514
-H) 5.92' (Hlbr, s, -NH-)7, 24-8
．． 17 (4H, aromatic ring H) HRMS value: 449.14
38 (M+) Example 15 (1) 2,6-dimetheru-4-(6-nitrophenyl)
Production of -1,4-dihydropyridine-'6,5-dicarboxylic acid bis(6-be/zenesulfonyloxyglobyl) ester Starting material: 2,6-dimethe-4-(6-nitrophenyl)-1,4- Dihydropyridine-6,5-dicarboxylic acid bis(6-hydroxypropyl) ester reaction conditions: benzenesulfonic acid chloride/triethylamine, THF yield 89.3%, pale yellow oil.

2.30 (6H,S, 2.6th position-CH5) 3.95~
4.22 (8H,m, -CH2CH,,CH2-X
2) 4.96 (H, s, 4th position H) 6, 18 (Hlbr, s, -Ndan-) 7.25~8
．． 10 (14H, aromatic ring ゛H) (2) Starting production of 2,6-dimethyl-4-(6-nitrophenyl)-1,4-dihydropyridine-6,5-dicarboxylic acid bis(3-nitroxypropyl) ester Substance: Sulfonic acid ester of (1) Reaction conditions: Tetra-n-butylammonium nitrate, dioxane, 60
°C, 15 hours Yield 82%, pale yellow prismatic crystals, melting point 16
5-136°c.

3372 (-NH-), 1694 (-Coo-)
, 1664.1275.878 (-CH02)2.3
7 (6H,s, 2.6th place=a(3)4,18 (4
H, t, J=7 Hzl-OCH2CH,,CH20
NO2X2) 4.42 (4H, t, J=7 Hz,
-CH20NO2X2) 5.08 (H, s14th position H) 6,06' (H, br, s, - Tsuiichi) 7.30~
8.18 (4H, aromatic ring H) H rhyme 8 value: 524.15
88 (M) 62 Example 16 (1) 2-(4-ethoxycarbonyloxyphenoxy)ethylmethane obtained in Example 16 (1) 8,709
Add. After reacting at room temperature for 1 hour, the mixture was neutralized with 10% hydrochloric acid. The residue obtained by distilling off the solvent was dissolved in chloroform, washed with water, dried, and the crude crystals obtained by distilling off the solvent were recrystallized from acetone-hexane, giving a melting point of 75.
．． 2-(4-hydroxyphenoxy)ethylmethanesulfone) 2.73 as colorless plate crystals at 0-75.5°C
．． ! i' (yield 80.7%) is obtained.

(2) 2.13 g of the obtained compound and tetra-n-
When 5.58 g of butylammonium nitrate was treated in the same manner as in Example 13 (2), 1.71 g of 2-(4-hydroxyphenoxy)ethyl nitrate was obtained as a colorless oil (yield 93.6%). ) is obtained.

6575.3300.1668.1279.847NM
R value: δCDC13 4,6111-4,84 (2H, m, -CH20NO
2) 6.75 (4H, s1 aromatic ring H) HRMS value: 199.0478 (M+) Example 17 (1) 5.8-dihydroxy-3,4-dihydro-
Add 10.9 g of 2H-l-benzopyrane in anhydrous tetrahedron, add dropwise a solution of 6.8 g of ethyl chlorocarbonate in 6 Q ml of anhydrous tetrahydrone to a solution of ice, and allow to react for 2 hours. Then BO ml of anhydrous tetrahydrone run and 9.7.9 ml of triethylamine are added and a solution of methanesulfonic acid chloride 1[], 3.9 ml in anhydrous tetrahydrofuran 60
ml was added dropwise and allowed to react for 1 hour. After further reacting at room temperature for 1 hour, the precipitate was removed, the solvent was distilled off, and the resulting residue was dissolved in ethyl acetate. After washing with dilute sodium bicarbonate solution and brine, drying, distilling off the solvent, and recrystallizing from acetone-ether, 8-ethoxycarbonyloxy-6-methanesulfonyloxy- 17.8.9 (yield 93.5%) of 3,4-dihydro-2H-1-benzopyran is obtained.

(2) 16 g of the obtained compound and 25 g of tetra-n-butylammonium nitrate were dissolved in 25 ml of toluene,
Stir for 28 hours at a bath temperature of 90°C.

The reaction mixture is dissolved in benzene, washed with water, dried, and then the solvent is distilled off. The resulting residue is subjected to silica gel column chromatography, and the benzene effluent is collected. When this is recrystallized from ether, 8-ethoxycarbonyloxy-6-nitroxy-6,4-dihydro-2H-l-benzopyran 9
4gC yield 80.7%) is obtained.

1759.1661.1280,87ON'MR value: δ
CDC13 1,64 (3H, t, J=7 Hz, -CH2CH
5) 2.84-3.48 (2H, m, C4-2H)
4, 1:2-4.54 (2H, m, C2-2H)4
．． 30 (2H, q, J = 7 Hz, -CH2C
H5) 5.32-5.55 (H, rn, C3-H)
6.76-7.15 (3H, m, aromatic ring H) HRMS
Value: 283.0690 (M+) Examples 18-21 The same compound as Example 17 was prepared by changing the reaction reagents. The results are shown below.

Example 18 (1) The following compound was produced using toluenesulfonic acid chloride in place of methanesulfonic acid chloride in Example 17 (1) (yield 95.6%).

Colorless needle crystals, melting point 118-119°C NMR value: δCDC13 2,80-6.28 (2Hlm, C4-2H)4.
03~4.36 (2H, m, C2-2H) 4.60
(2H, q, J = 7 Hz, -CH2CH5)
4.84-5.08 (H, m, C3-H) 6.76
~7.10 (3H, m, (, ~7-3H)7.24
~7.44 (2H, d,, J=8Hz, aromatic ring H)7
．． 70-7.90 (2H, d, , J = 8Hz, aromatic ring H
)(2) The compound obtained in (1) and tetra-n-
Dissolve butylammonium nitrate in dioxane and
When reacted at ℃ for 25 hours, the compound of Example 17 (2) is obtained (yield: 88.2%).

Example 19 (1) Using benzenesulfonic acid chloride as a substitute for methanesulfonic acid chloride in Example 17 (1), 8-
Ethoxycarbonyloxy-3-benzenesulfonyloxy-6,4-dihydro-2H-1-benzopyran was produced (yield 97%). Colorless oil.

NMR value: δCDC13 1,36 (6H, tlJ ~7 Hz, -〇H2CH
3) 2.80-3.28 (2Hlm, C, -2H)
4.05-4.36 (2H, m, C22H) 4.3
0 (2H, q, J ~7 Hz, -CH2CH5
)4.90-5.15 (H,m,C3,-H)6.
8 D~7. IO(3H, m, Ca ~7
3H) 7.44-7.80 (3H, m, aromatic ring H)
7, 85-8.04 (2H, m, aromatic ring H) (2)
When the compound obtained in (1) and tetra-n-butylammonium nitrate are dissolved in toluene and reacted at 80°C for 18 hours, the compound of Example 17 (2) is obtained (
Yield 92.5%).

Example 20 (1) 3-hydroxymethyl-8-hydroxy-3
,4-dihydro-2H-l-benzopyran in Example 17
When treated in the same manner as in (1), 8-ethoxycarbonyloxy-6-methanesulfonyloxymethyl-3,4-dihydro-2H-1-benzopyran is obtained as a colorless oil (yield 92.5%).

NMR value: δCDCl.

IJ 8 (6H, tlJ ~7 Hz, -CH2CH
5) 2.40-5.20 (6H,m, c3-H,C
, -2H)6.00 (6H,s, =So2CH3)
4.00~4.50 (6H, m, C2-2H, -C
H2OSO2-1-0 ship CH3) 6.78-7.16 (3H, ms C, 7-3H) (2
) When the compound obtained in (1) and tetra-n-butylammonium nitrate were dissolved in toluene and reacted at 90°C for 6 hours, 8-ethoxycarbonyloxy-3-nitroxymethyl-3, 4-dihydro-2H-l-benzo-69 = bilane is obtained.

1759 (-0C0OC2H,), 1668.127
6.850 (-ONO2) NMR value: δCDC13 1,67 (3H, t, J=7Hz, -CH2C'H
A) 2.32-3.16 (3H, m, C4-2H,
C8-H) 3.92-4.44 (2Hlm, C2-
2H) 4.26 (2H, q, J=7 Hz, -CH
, CH3) 4.43 ('2 H,a, J=7 Hz
l-CH2ONO2)6.66~7.02 (3H, m
, C, ~7-3H) Example 21 Example 20 When the compound obtained in (1) and benzyl-tri-n-butylammonium nitrate were dissolved in acetonitrile and reacted at 80°C for 28 hours, Example 20
(The same compound as 21 is obtained (yield 91.5%).

Example 22 (1) N-(2-hydroxyethyl)nicotinia Stir at room temperature for 40 minutes. Next, 6.49 g of tetraethylammonium nitrate was added, and the mixture was stirred and reacted for 4 hours at a bath temperature of 65°C. After the reaction is completed, the solvent is distilled off, and the resulting residue is partitioned by adding water and ethyl acetate, and then diluted aqueous sodium bicarbonate is added to make it slightly alkaline, and the ethyl acetate layer is separated. After washing with saturated brine and drying, the solvent is distilled off, and the resulting residue is subjected to silica gel column chromatography to obtain crude crystals from the ethyl acetate effluent.

When recrystallized from ethyl acetate-ether, the melting point is 91-9.
N-(2-hydroxyethyl)nicotinamide nitrate) 1.489 (yield 7) as colorless needles at 2°C
7.6%) is obtained.

3261.1629.1287.859NMR value: δC
DC13 3,78 (2H, qlJ ~6 Hz, -CONHC
HL-)4.65 (2H,t, J ~6 H2,-
CH2ONO2)7,35 (H, d', d, J
-8Hz, J==5Hz, c, H) 7.94
(H,',br,t,, -NH-)8.1o (H
, a, t, J=8H2, J=2H2, C, -H)8
．． 66', (H, d, d, J=5Hz, J=2Hz, C
6-H) 8.96 (H, d, J=2Hz, C2-H)
HRMS value: 212.0669 (M+1) Example 26
~25 The following compound can be produced in the same manner as in Example 22.

Example 26 Starting alcohol reaction conditions Niacetonitrile/pyridine (CH3SO4) 20, 0.5 hours Tetra-n-butylammonium nitrate, 50°C, 1.5 hours Pale yellow oil, yield 66.1% 3454.1629. 1277.857NMR value: δC
DC13 2,30 (3H,s, C,, -CH5) 3.02
(2H, tlJ = 7 Hz, -CHXCH,, ON
O,,) 3.78 (6H, s, CH, 0-) 4.50 (2H, t, J = 7 Hz, -CH2
CH,, ONO,,)6.68 (H, d, d, J
-=8Hz, 2Hz, c, -H)6.82 (H,
d, J ==2Hz, C4-H)7,04 (Hla
, J=8, C7-H) HRMS value: 25[+, ()
946 (M'+) Example 24 Starting alcohol reaction conditions Niacetonitrile/pyridine to 43- (CH3SO4) 2011 hours Tetraethylammonium nitrate, 65°G 13 hours Product: Colorless needles, melting point 126°C, yield 66.4 %6295
(-CONH-), 1640.1281.863(-O
NO2) NMFt value: δCDC13 3,83 (2H,, q, J=6, -NHCH,, -)
4.68 (2H, t, J = 6, CH2C pull 0NO
2), 6.05 (2H1s, OCH20), 7, 0
0 (H, s, C"H), 7, 55 (H, d, J=5 H2, C4-H), 8
．． 23 (H, d, J = 5Hz, , C3-H), 8
．． 58 (H, b, r, tl-Ndan-), HRMS value:
305. [1634 (M) Example 25 Starting alcohol reaction conditions Nidioxane/pyridine (CH3S02) 2o, 5 minutes Tetra-n-butylammonium nitrate, 80°C, 6 hours Product: Yield 65.6 Physical properties are Example 8 Same as Example 26 2-(t,-butoxycarbonylamino)-2',6'-dimethyl-4'-(2
-methanesulfonyloxyethoxy)probiog is added and refluxed under stirring at 90°C for 40 hours.

After the reaction is complete, the resin is removed and extracted with ethyl acetate/acetone. When the residue obtained by distilling off the solvent under reduced pressure is recrystallized from ethyl acetate-hexane, the melting point is 112-116°.
As a colorless prism crystal of C, 2-(t;-butoxycarbonylamino)-2',6'-dimethyl-4'-(2-
Nitroxyethoxy)propionanilide 35.09
(Yield: 88%) is obtained.

Analytical values were consistent with the product of Example 1.

Examples 27-32 By the resin method of Example 26, Examples 2.6.7.16.
14.15.17 and 2o are prepared. That is, they are shown in the table below for sulfonic acid esters.

Example 35 6-Pyricine Propanol 5481n9 was dissolved in acetonitrile 'lQml, Amberlystom-26 Nitrate (ONo2 type) 6.0.9 and Molecular Sieve 65
．． 1. Add methanesulfonic acid anhydride in the presence of 0.0 g and stir at room temperature for 30 minutes and at 60° C. for 30 minutes. After the reaction is complete, Amberlyst A-26 and Molecular Sieve 6X are removed, and the solvent is distilled off under reduced pressure. 6-(6-pyridyl)probyl nitrate) as a yellow oil.
440 mg (yield 61%) is obtained. The analytical values were the same as in Example 11.

Example 36 N-(2-hydroxyethyl)nicotinamide 831m
9 and treated in the same manner as in Example 36, the melting point was 9.
N-(2-hydroxyethyl)nicotinamide nitrate 810 m9 (yield 7
6%) is obtained. The analytical values were the same as in Example 22.

Example 37 (1) 8-hydroxy-(6R)-nitroxy-6,4
-Dihydro-2H-l-benzopyran 1.24g was dissolved in ethanol 36ml, 10% palladium carbon 0.4g
g and stirred for 1.5 hours under a hydrogen stream. After the reaction,
When the residual aroma obtained by removing the catalyst and distilling off the solvent is recrystallized from ethyl acetate, (3R), 8-dihydroxy-3,4- Dihydro-2H-l-benzopyran 956
m9 (yield 97.9%) is obtained.

Cα]p5-45.8' (c = 3, tetrahydrofuran)36O NMR value: δCD30D 2.52-3.18 (2H, m, C4-2H)3.
80-4.28 (3H, m, C2-2H, C3-H
) 6.44-6.78 (3Hlm, aromatic ring H) MS value: m/z 166 (M) (2) Obtained (3R), 8-dihydroxy form 1.
Using 66 g, the following treatment was carried out in the same manner as in Example 19 (1). 96.8%) is obtained.

[α];' = -21, Do (c = 2.4, chloroform) (31 obtained using ureta (3R)-benzenesulfonyl compound 1°809, treated in the same manner as in Example 19 (2), 8-Ethoxycarbonyloxy-(3S)-nitroxy-6,4-dihydro-2H-l-benzopyran 1
．． 11 g (yield 82.3%) are obtained. This was dissolved in 16 ml of methanol, and 2.0 g of a 10% aqueous sodium hydroxide solution was added while cooling with ice water.

After reacting at room temperature for 60 minutes and neutralizing by adding 5% hydrochloric acid, methanol is distilled off and the residue obtained is extracted with chloroform. After washing the chloroform layer with water and drying it, the chloroform was distilled off, and the residual aroma was subjected to silica gel column chromatography and eluted with chloroform. When this effluent was recrystallized from ethyl acetate-hexane, the melting point was 1290~
8-Hydroxy-(6S)-nitroxy-3,4-dihyde I:l-2H as colorless prism crystals at 130.5°C
-1-benzopyran 7061n9 (yield 85.3%) is obtained.

[α)--40.4° (c=1.46, chloroform)
5330 (OH), 1620.1290 (-ONO2
) NMR value: δCDCl3 2.84-3.42 (2H, m1C4-2H) 4.1
2~4.52 (2H, m, C2-2H) 5.32~
5.50 (H, m, C3-H) 5.44 (H, s,
-0H) 6.48 to 6.90 (6H, m, aromatic ring H) The physical properties of the 3H isomer used as a raw material are as described in Japanese Patent Application No. 59-6217.
Although it is as described in the specification of No. 7, it is shown below.

Melting point: 129.0-130.5°C [α) = +40.8° (c-3, chloroborum) 3
330 (OH), 1620.1290 (-ONf)2
) NMR value: δcDc13 When the obtained 38 bodies, which are the same as the 3S body described above, are treated in the same manner as the raw material, 3H
You can get a body.

The physical properties of 38 products produced from N-methyl-D-phenylalanine derivatives according to the method described in Japanese Patent Application No. 59-36178 are as follows.

8-Hydroxy-(3S)-nitroxy-3,4-dihydro-2H-l-benzopyran Melting point: 129.0-130.5°C [“]ゎ=-40.8° (c-3, chloroform) 33
30 (oH), 1620.1290 (-ONO2)
.

NMR value: δCDCl3 Same as the above 6S form Example 38 (6R)-benzenesulfonyloxy-8-ethoxycarbonyloxy-6,4- produced in Example 37 (2)
Dihydro-2H-l-benzopyran 378 M+9 was dissolved in 10 ml of toluene, and Amberlyst A-26 nitrate (ONO□ type) 2.5, . The mixture was heated and stirred at 90° C. for 72 hours in the presence of 9. After the reaction, the same treatment as in Example 26 was carried out to obtain 8-ethoxycarbonyloxy-(38)-nitroxy-6,4-dihydro-2H-l-benzopyran 1
82■ (yield 64%) was obtained.

Next, this was dissolved in 2.6 rnl of methanol, and 0.3 g of a 10% aqueous sodium hydroxide solution was added under ice-water cooling.
Let react for 20 minutes at room temperature. After the reaction is completed, the mixture is neutralized with a 5% aqueous hydrochloric acid solution, the solvent is distilled off, and the residual aroma obtained is extracted with chloroform. After washing the chloroform layer with water and drying it,
When the solvent was distilled off and recrystallized from ethyl acetate-m-hexane, 8-hydroxy-(6S)-nitroxy-3,
111 lbs of 4-dihydro-2H-l-benzopyran (yield 82.4%) is obtained.

The physical properties of this product were completely consistent with those produced in Example 37.

Claims (1)

[Claims] 1. A nitric acid esterification method characterized by reacting a sulfonic acid ester with an organic quaternary ammonium nitrate. 2. The method according to claim 1, characterized in that a sulfonic acid ester obtained by converting an alcohol into a sulfonic acid ester is used.