JPH08151342A - Production of enol ether derivative - Google Patents

Abstract

PURPOSE: To simply obtain an enol ether compound by reacting a specific compound having hydroxyl group with an alkylating or a silylating reagent. CONSTITUTION: A compound of formula I [R<1> to R<3> are each H, an alkyl or an aryl and any two thereof together may form a cycloalkyl; R<5> is an alkyl or a cycloalkyl; R<5> and R<7> are each H, an alkyl or an aryl; Ar is an aryl] is reacted with an alkylating or a silylating reagent of the formula R<8> -X [R<8> is an alkyl or a group of Si(R<10> , R<11> , R<12> ); R<10> to R<12> are each an alkyl; X is a halogen, an alkyl, etc.] in the presence of a base (e.g. potassium t-butoxide in a solvent (e.g. DMSO) to afford a compound of formula II, which can be converted into a 1,2-dioxetane derivative capable of manifesting the chemiluminescence by reaction thereof with singlet oxygen. The 1,2-dioxetane derivative is excellent in thermal stability, capable of carrying out the measurement in a short time and readily applicalbe to high-sensitivity analytical systems.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention has the general formula

[Chemical 10] (In the formula, R ¹ , R ² and R ³ are a hydrogen atom, an alkyl group or an aryl group, and any two members of R ¹ , R ² and R ³ can be combined to form a cycloalkyl group. .R ⁵ is an alkyl group or a cycloalkyl group .R ⁶
And R ⁷ is a hydrogen atom, an alkyl group or an aryl group, R ⁸¹³ is a hydrogen atom or a group represented by R ⁸ and R ¹³ , and R ⁸ is an alkyl group or Si (R ¹⁰ , R ¹¹ , R ¹² )
The group represented by R ¹³ is an alkyl group or an aryl group. Ar is an aryl group which is unsubstituted or substituted with R ⁹ , and R ⁹ is an alkoxyl group or —OSi (R ¹⁰ , R ¹¹ ,
It is a group represented by R ¹² ). R ¹⁰ , R ¹¹ and R ¹² are alkyl groups. ) Relates to a method for producing an enol ether compound. The enol ether compound represented by the general formula (I) converts the alkoxyl group of R ⁹ into a hydroxyl group, if necessary, and then -OSi (R ¹⁰ , R ¹¹ , R 2
^By converting the group represented by ¹² ) or a phosphate group and then reacting with singlet oxygen, a 1,2-dioxetane derivative which is a chemiluminescent substance used in a chemiluminescent immunoassay can be obtained ( See the reference example below).

[0002]

2. Description of the Related Art Conventionally, there is no report that a compound represented by the above general formula (I) has been produced.
No. 918 or Japanese Patent Publication No. 5-45590 discloses a production example of a compound having an OR ⁵ and Ar group in which a bulky adamantyl group of the general formula (I) is spiro-bonded.

[0003]

However, it has been extremely difficult to introduce a functional group such as OR ^{813 by} the conventional production method.

[0004]

Means for Solving the Problems As a result of diligent efforts made on the method for synthesizing the compound represented by the general formula (I), the present inventors have found a simple method for synthesizing a luminescent compound having a functional group, The present invention has been completed.

The present invention will be described below in accordance with the reaction formula.

[Chemical 11] (In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and Ar are the same as the above, and R ⁸¹³ is a group represented by R ⁸ and R ^13. )

<Step 1-1> In this step, the compound represented by the general formula (II) is added to the compound represented by the general formula (II) in the presence of a base.
The compound represented by the general formula (V) is produced by reacting the alkylating reagent represented by I).

The above-mentioned general formula (II) of the raw material used in this step
The compound represented by, for example, a method of reacting a β-ketoester and an alkyl halide in the presence of a base or a Lewis acid,

[Chemical 12] Method of reacting aromatic carboxylic acid derivative and acetic acid ester in the presence of base

[Chemical 13] Alternatively, a method of reacting an aromatic ketone with a chlorocarbonic acid ester or a carbonic acid ester

Embedded image Is a compound that can be easily produced by using.

On the other hand, examples of the alkylating reagent for introducing R ⁵ represented by the general formula (III) include halides such as chlorine, bromine and iodine, methanesulfonyloxy, benzenesulfonyloxy and p-toluenesulfonyloxy. Substituted sulfonyl oxides such as and the like, and dialkyl sulfates such as dimethyl sulfate and diethyl sulfate can be used.

It is an essential requirement that this step be performed in the presence of a base. Examples of usable bases include alkali metal alkoxides or alkaline earth metal alkoxides such as sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium t-butoxide, and diethoxymagnesium, lithium hydride, sodium hydride, hydrogen. Alkali metal or alkaline earth metal hydrides such as potassium hydride and calcium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide,
Examples thereof include alkali metal or alkaline earth metal hydroxides such as barium hydroxide, and alkali metal carbonates such as sodium carbonate and potassium carbonate.

The reaction includes ethers such as THF, dioxane and DME, DMF, DMA, N-methylpyrrolidone (N
MP), amides such as HMPA, DMSO, sulfolane, water and the like, alone or in a mixed solvent thereof.

The process can be carried out in the presence of a phase transfer catalyst such as tetraalkylammonium salt or crown ether.

<Step 1-2> In this step, the compound represented by the general formula (II) is reacted with the alcohol represented by the general formula (IV) in the presence of an acid catalyst to produce the compound represented by the general formula (IV). V) for producing the compound represented by the formula (V).

It is an essential requirement that this step be carried out in the presence of an acid catalyst. Examples of the acid catalyst include mineral acids such as hydrochloric acid, sulfuric acid and phosphoric acid, benzenesulfonic acid, p-
Organic sulfonic acids or organic sulfonates such as toluene sulfonic acid, trifluoroboron diethyl ether complex, Lewis acids such as trichloroboron, tribromoboron, lead chloride and aluminum chloride can be used.

The reaction includes aromatic hydrocarbons such as benzene, toluene and xylene, dichloromethane, chloroform,
It can be carried out in a solvent such as carbon tetrachloride, halogenated hydrocarbons such as 1,2-dichloroethane, ethers such as THF, dioxane and DME.

<Second Step> In this step, the compound represented by the general formula (V) obtained in the first step 1-1 or the second step 1-2 is reduced or reacted with an organolithium reagent or a Grignard reagent. According to the above general formula (VI
It is for producing a compound represented by I).

Examples of the compound to be reacted with the compound (V) include diisobutylaluminum hydride,
Reducing agents such as lithium aluminum hydride, sodium aluminum hydride and sodium borohydride, or methyl lithium, ethyl lithium, propyl lithium, butyl lithium, pentyl lithium, hexyl lithium,
Alkyl lithium compounds or aryl lithium compounds such as heptyl lithium, octyl lithium, phenyl lithium, methyl magnesium chloride, methyl magnesium bromide, ethyl magnesium chloride,
Ethyl magnesium bromide, propyl magnesium chloride, propyl magnesium bromide, butyl magnesium chloride, butyl magnesium bromide, pentyl magnesium chloride, pentyl magnesium bromide, hexyl magnesium chloride,
Alkyl magnesium halide compounds such as hexyl magnesium bromide, heptyl magnesium chloride, heptyl magnesium bromide, octyl magnesium chloride, octyl magnesium bromide, phenyl magnesium chloride and phenyl magnesium bromide, or aryl magnesium halide compounds.

The reaction includes aromatic hydrocarbons such as benzene, toluene, xylene, diethyl ether, DME, TH.
Ethers such as F, dioxane and diglyme, and saturated hydrocarbons such as heptane, hexane and pentane can be used alone or in a solvent mixture thereof.

<Step 3-1> In this step, the compound represented by the general formula (VII) obtained in the second step is added to the compound of the general formula

[Chemical 15] (In the formula, R ⁸ is an alkyl group or Si (R ¹⁰ , R ¹¹ , R ¹² )
When R ⁸ is an alkyl group, X is a halogen atom, an alkyl or aryl sulfonyloxy group or an alkylsulfate group, and R ⁸ is Si (R ¹⁰ ,
In the case of the group represented by R ¹¹ and R ¹² ) it is a halogen atom. ) By reacting with an alkylating reagent or a silylating reagent,

Embedded image (In the formula, R ¹ , R ² , R ³ , R ⁵ , R ⁶ , R ⁷ and Ar are the same as the above, and R ⁸ is an alkyl group or Si (R ¹⁰ , R ¹¹ ,
It is a group represented by R ¹² ). ) The compound represented by these is manufactured.

The above-mentioned general formula (VIII) which is a raw material in this step
When the compound represented by is an alkylating reagent,
The compounds exemplified in 1 step can be used.

Further, this step is essentially required to be carried out in the presence of a base, and the base exemplified in the step 1-1 can also be used for this base.

Regarding other reaction conditions and the like, the same conditions as those in the step 1-1 can be adopted and carried out. When the compound represented by the general formula (VIII) is a silylating reagent, an amine such as pyridine, triethylamine or imidazole can be used as the base. The reaction is
Ethers such as THF, dioxane and DME, nitriles such as acetonitrile and propionitrile, hexane,
Hydrocarbons such as benzene and toluene, dichloromethane,
It can be carried out in a solvent such as halogenated hydrocarbons such as chloroform and 1,2-dichloroethane and amides such as DMF, DMA and NMP.

<Step 3-2> In this step, the compound represented by the general formula (VII) obtained in the second step is reacted with a halogenating reagent in the presence of a base, or an alkyl or aryl sulfonyl chloride is used. And are reacted in the presence of a base, and then the general formula

[Chemical 17] (In the formula, R ¹³ is an alkyl group or an aryl group.) An alcohol represented by the general formula is obtained by reacting the alcohol in the presence of a base.

Embedded image (In the formula, R ¹ , R ² , R ³ , R ⁵ , R ⁶ , R ⁷ , Ar and R ¹³
Is the same as above. ) The compound represented by these is manufactured.

As the halogenating reagent to be reacted with the compound represented by the general formula (VII), for example, thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, thionyl bromide, phosphorus tribromide, etc. are used. can do. The reaction needs to be carried out in the presence of a base, and amines such as pyridine and triethylamine can be preferably used. The reaction is preferably carried out in a solvent, for example, hydrocarbons such as hexane, benzene, toluene, xylene, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, THF, dioxane,
Ethers such as DME, esters such as methyl acetate and ethyl acetate, and amides such as DMF, DMA and NMP can be used.

As the alkyl or aryl sulfonyl chloride reacted with the compound represented by the general formula (VII), for example, methane sulfonyl chloride, benzene sulfonyl chloride, p-toluene sulfonyl chloride and the like can be used. The reaction requires the presence of a base as in the case of reacting a halogenating reagent, and the amines described above can be used. With respect to the solvent, the same solvent as that used for reacting the halogenating reagent can be used to carry out the reaction.

In this step, after subjecting to any of the above reactions, the desired product is isolated or without isolation.
The reaction is performed with the alcohol represented by the general formula (IX).

The reaction needs to be carried out in the presence of a base,
The base exemplified in Step 1-1 can be used. As the solvent used for the reaction, the solvent exemplified in Step 1-1 can be used.

[0027]

EXAMPLES The present invention will be described in more detail with reference to Examples and Reference Examples.

(Reference Example 1)

[Chemical 19]

Dried zinc chloride 4.99 g (37 mmol) and ethyl benzoylacetate (Compound [1]) 14.6 g (76 m) in anhydrous dichloromethane 30 ml at room temperature under nitrogen atmosphere.
mol) and t-butyl chloride 16.5 ml (152 mm)
ol) was added and the mixture was heated under reflux overnight. The reaction mixture was poured into saturated saline and extracted with dichloromethane. The extract layer was dried over magnesium sulfate, concentrated, and distilled under reduced pressure.
Ethyl benzoyl-2-t-butylacetate (Compound [2]) was obtained at 8.76 g in a yield of 46.5%.

Mp45-47 ° C / bp 89-90 ° C
(0.4 mmHg) ¹ HNMR (400 MHz, CDCl ₃ ); δ 1.16
(S, 9H), 1.17 (t, J = 7.2Hz, 3H), 4.
13 (q, J = 7.2Hz, 2H), 4.31 (s, 1
H), 7.26 to 7.96 (m, 5H) ppm IR (KBr); 3368, 3173, 3067, 16
62, 1624, 1404, 686 cm ^-1 Mass (m / z,%); 248 (M ⁺ , 1), 192 (10
0), 146 (10), 105 (58), 77 (2)

(Example 1)

Embedded image

Compound [2] 6.23 synthesized in Reference Example 1
g (25 mmol) was added to 50 ml of anhydrous DMSO, and potassium t-butoxide was added to the solution stirred at room temperature under a nitrogen atmosphere.
61 g (50 mmol) was added and stirred for 30 minutes. The solution was cooled to 0 ° C. and 4.75 ml (50 mmol) dimethylsulfate was added.
After adding, the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into saturated saline and extracted with ethyl acetate. The extract layer was washed with saturated brine, dried over magnesium sulfate, and concentrated. The concentrate was applied to a silica gel column and poured out with a mixed solvent of dichloromethane and hexane 1: 2, and ethyl 2-t-butyl-3-methoxy-3-phenyl-2-propenoate (Compound [3]) was mixed with 3%. It was obtained in a yield of 0.46 g and a yield of 52.6%.

¹ HNMR (400 MHz, CDCl ₃ ); δ
0.86 (t, J = 6.8Hz, 3H), 1.30 (s, 9
H), 3.30 (s, 3H), 3.81 (q, J = 6.8H
z, 2H), 7.26 to 7.34 (m, 5H) ppm IR (liquid film); 2959, 1718, 129
6,1072 cm ^-1 Mass (m / z,%); 262 (M ⁺ , 43), 247 (10
0), 187 (30), 105 (30), 87 (17), 7
7 (15)

(Example 2)

[Chemical 21]

Compound [3] 5.24 synthesized in Example 1
g (20 mmol) was added to 10 ml of anhydrous toluene, and the mixture was stirred at -78 ° C under a nitrogen atmosphere. 29.2 ml of diisobutylaluminum hydride (1.5M toluene solution) was added to this solution.
(44 mmol) was added and stirred for 1 hour. The reaction mixture was poured into saturated saline and extracted with ethyl acetate. The extract layer was washed with saturated brine, dried over magnesium sulfate, and concentrated.
2-t-butyl-3-methoxy-3-phenyl-2-propen-1-ol (Compound [4]) was 3.99 g,
Obtained as a colorless amorphous solid in a yield of 90.7%.

¹ HNMR (400 MHz, C ₆ D ₆ ); δ
1.48 (s, 9H), 3.01 (s, 3H), 3.86
(D, J = 4.8 Hz, 2 H), 7.06 to 7.31 (m,
5H) ppm IR (KBr); 3285, 2957, 1633, 12
92, 1113, 1010, 696 cm ^-1 Mass (m / z,%); 220 (M ⁺ , 35), 205 (3
0), 187 (65), 163 (56), 105 (63),
77 (100)

(Reference Example 2)

[Chemical formula 22]

210 mg of the compound [4] synthesized in Example 2
(0.95 mmol) and 5 mg of TPP in dichloromethane 1
It was dissolved in 0 ml and stirred at 0-5 ° C under an oxygen atmosphere. This solution was irradiated with a Na lamp (940 W) for 1 hour. The reaction mixture was concentrated, subjected to preparative TLC and developed with a 10: 1 mixture of hexane and diethyl ether to give 3
-T-butyl-3-hydroxymethyl-4-methoxy-
4-phenyl-1,2-dioxetane (compound [5])
Was isolated as a yellow oil in a yield of 86 mg and a yield of 35.8%.

¹ HNMR (400 MHz, C ₆ D ₆ ); δ
0.59 (t, J = 7.3 Hz, 1 H), 1.43 (s, 9
H), 2.80 (s, 3H), 3.83 (q _AB , J = 7.3
Hz, 2H), 7.00 to 7.48 (m, 5H) ppm IR (liquid film); 3584, 2966, 145
0, 1249, 1107, 1041, 706 cm ^-1 Mass (m / z,%); 253 (M ⁺ +1, 0.5), 220
(22), 205 (8), 187 (11), 163 (1
1), 136 (19), 117 (8), 105 (67), 8
5 (16), 77 (44), 55 (100)

(Example 3)

[Chemical formula 23]

0.24 g (6 mmol) of sodium hydride, 1.16 g (5 mmol) of the compound [4] synthesized in Example 2 and 0.38 ml (6 mmol) of methyl iodide were added to 10 ml of anhydrous THF at 0 ° C. under a nitrogen stream. Sequentially added, followed by heating under reflux for 3 hours. The reaction mixture was poured into saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The extract layer was washed with saturated brine, dried over magnesium sulfate, and concentrated to give 2-t-
Butyl-1,3-dimethoxy-1-phenyl-1-propene (compound [6]) was obtained as a yellow oil in a yield of 1.15 g of 93.2%.

¹ HNMR (400 MHz, C ₆ D ₆ ); δ
1.07 (s, 9H), 2.98 (s, 3H), 3.05
(S, 3H), 3.65 (s, 2H), 7.07 to 7.39
(M, 5H) ppm IR (liquid film); 2955, 1086, 704 cm
^-1 Mass (m / z,%); 234 (M ⁺ , 17), 219 (1
4), 203 (27), 187 (32), 177 (35),
163 (31), 147 (32), 121 (76), 10
5 (95), 77 (100), 55 (71)

(Reference Example 3)

[Chemical formula 24]

100 mg of the compound [6] synthesized in Example 3
(0.43 mmol) and 5 mg of TPP in dichloromethane 1
It was dissolved in 0 ml and stirred at 0-5 ° C under an oxygen atmosphere. This solution was irradiated with a Na lamp (940 W) for 1 hour. The reaction mixture was concentrated, subjected to preparative TLC and developed with a 10: 1 mixture of hexane and diethyl ether to give 3
-T-butyl-4-methoxy-3-methoxymethyl-4
77 mg of -phenyl-1,2-dioxetane (compound [7]) was isolated as a yellow oily substance in a yield of 67.7%.

¹ HNMR (400 MHz, C ₆ D ₆ ); δ
1.50 (s, 9H), 2.35 (s, 3H), 2.85
(S, 3H), 3.58 (q _AB , J = 6.0Hz, 2H),
7.05 to 7.59 (m, 5H) ppm IR (liquid film); 2932, 1450, 125
5,1099,975,704 cm ^-1 Mass (m / z,%); 234 (M ⁺ -32,3), 187.
(2), 177 (4), 136 (25), 130 (10),
105 (72), 85 (14), 77 (46), 55 (1
00)

(Reference Example 4)

[Chemical 25]

13.0 ml of diisopropylamine (92.8
butyllithium (1.62M hexane solution) (55.0 ml, 89.1 mmol) was added to 75 ml of anhydrous THF in an argon atmosphere at room temperature under stirring and stirred for 30 minutes. This solution was cooled to −78 ° C., 15.0 ml (89.5 mmol) of ethyl t-butyl acetate was added, and the mixture was stirred for 20 minutes, and subsequently, methyl 3-methoxybenzoate [8] 10.
05 g (60.5 mmol) was added. This solution is -78 ° C
The mixture was stirred for 2 hours and 40 minutes at 0 ° C. and then at 0 ° C. for 1 hour and 30 minutes. The reaction mixture was poured into 1N hydrochloric acid and extracted with ethyl acetate. The extract layer was washed with saturated brine, dried over magnesium sulfate, and concentrated. When the concentrate was applied to a silica gel column and flushed with dichloromethane, 2-t-butyl-2
-(3-Methoxybenzoyl) ethyl acetate (compound

[9]) was obtained as a colorless oily substance in a yield of 12.24 g and a yield of 72.7%.

¹ HNMR (300 MHz, CDCl ₃ ); δ
1.15 (s, 9H), 1.18 (t, J = 7.2Hz, 3
H), 3.86 (s, 3H), 4.13 (q, J = 7.2H)
z, 2H), 4.28 (s, 1H), 7.11 (d with fine
coupling, J = 8.3Hz, 1H), 7.37 (dd, J
= 8.3 and 7.6Hz, 1H), 7.48 (s with fine
coupling, 1H), 7.54 (d, J = 7.6Hz, 1H)
ppm IR (liquid film); 2964, 2912, 173
6,1696,1598,1582 cm ^-1 Mass (m / z,%); 278 (M ⁺ , 10), 222 (2
6), 176 (18), 135 (100)

(Example 4)

[Chemical formula 26]

Compound synthesized in Reference Example 4

[9] 1.30
g (4.68 mmol) was added to 10 ml of anhydrous DMSO, and 1.02 g (9.09 mmol) of potassium t-butoxide was added to the solution stirred at room temperature under a nitrogen atmosphere and stirred for 15 minutes. The solution was cooled to 0 ° C and 0.80 ml of dimethyl sulfate (8.4
4 mmol) was added dropwise and the mixture was stirred for 50 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The extract layer was washed with saturated brine, dried over magnesium sulfate, and concentrated. The concentrate was applied to a silica gel column and poured out with a mixed solvent of hexane and ethyl acetate at a ratio of 15: 2. As a result, ethyl 2-t-butyl-3-methoxy-3- (3-methoxyphenyl) -2-propenoate (compound [10]) 1.15 g, yield 84.2
% As a colorless oil.

¹ HNMR (300 MHz, CDCl ₃ ); δ
0.91 (t, J = 7.1 Hz, 3 H), 1.29 (s, 9
H), 3.33 (s, 3H), 3.80 (s, 3H), 3.8
6 (q, J = 7.1Hz, 2H), 6.81 to 6.96
(M, 3H), 7.22 (t, J = 7.8Hz, 1H) ppm IR (liquid film); 2960, 1720, 163
4, 1598, 1580 cm ^-1 Mass (m / z,%); 292 (M ⁺ , 60), 278 (3
1), 277 (100), 247 (21), 231 (2
1), 135 (35)

(Example 5)

[Chemical 27]

Compound [10] 2.4 synthesized in Example 4
9 g (8.53 mmol) was added to 30 ml of anhydrous toluene, and the mixture was stirred at -78 ° C under an argon atmosphere. Diisobutylaluminum hydride (25% toluene solution) 1
0.0 ml (17.6 mmol) was added and the mixture was stirred for 1 hour and 20 minutes. Methanol was added to the reaction mixture until foaming disappeared, the mixture was poured into a mixed solution of water and ethyl acetate, filtered through Celite, and the organic layer was separated. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated to give 2-t-butyl-3-methoxy-3- (3-methoxyphenyl) -2-
Propen-1-ol (Compound [11]) was 2.08
g as a colorless oil with a yield of 97.6%.

¹ HNMR (300 MHz, CDCl ₃ ); δ
1.32 (s, 9H), 3.24 (s, 3H), 3.82
(S, 3H), 3.94 (d, J = 5.5Hz, 2H), 6.
85-6.95 (m, 3H), 7.24-7.32 (m, 1
H) ppm IR (liquid film); 3464, 2956, 163
6,1598,1580 cm ^-1 Mass (m / z,%); 250 (M ⁺ , 67), 235 (8
9), 219 (35), 217 (73), 193 (10
0), 187 (21), 135 (28), 133 (27)

(Example 6)

[0056]

[Chemical 28]

Compound [11] 2.5 synthesized in Example 5
0 g (10.0 mmol) was added to 15 ml of anhydrous DMF, and the mixture was stirred at room temperature under an argon atmosphere. To this solution was added 60% sodium hydride (420 mg, 10.5 mmol) and 110 ° C
The mixture was heated and stirred for 10 minutes. To this solution was added neopentyl bromide (1.50 ml, 11.9 mmol) and the mixture was heated at 110 ° C for 2 hours.
The mixture was heated and stirred for an hour. The reaction mixture was poured into water and extracted with ethyl acetate. The extract layer was washed with saturated brine, dried over magnesium sulfate, and concentrated. Apply the concentrate to a silica gel column,
When it was poured out with a mixed solvent of hexane and ethyl acetate of 10: 1, 2-t-butyl-1-methoxy-1- (3-
Methoxyphenyl) -3-neopentyloxy-1-propene (compound [12]) was obtained as a colorless oily substance in a yield of 2.18 g and 68.1%.

¹ HNMR (300 MHz, CDCl ₃ ); δ
0.91 (s, 9H), 1.27 (s, 9H), 2.83
(S, 2H), 3.25 (s, 3H), 3.61 (s, 2
H), 3.81 (s, 3H), 6.86 (ddd, J = 8.
2, 2.6 and 1.0Hz, 1H), 6.92 (s with fi
ne coupling, 1H), 7.00 (d with fine couplin
g, J = 7.5 Hz, 1 H), 7.23 (dd, J = 8.2 a
nd 7.5Hz, 1H) ppm IR (liquid film); 2956, 2868, 163
6,1598,1580 cm ^-1 Mass (m / z,%); 320 (M ⁺ , 31), 263 (7)
3), 249 (19), 234 (19), 233 (43),
219 (42), 217 (41), 203 (21), 19
3 (100), 187 (21), 177 (29), 121
(29), 111 (25), 97 (33), 83 (28),
71 (37), 57 (55)

(Reference Example 5)

[Chemical 29]

530 mg of 60% sodium hydride (13.
3 mmol) in 20 ml of anhydrous DMF under argon atmosphere at 0
1.0 ml of ethanethiol (13.5
mmol) was added. After stirring this solution at room temperature for 30 minutes, 2.16 g (6.75 mm) of compound [12] synthesized in Example 6 was used.
ol) was dissolved in 15 ml of anhydrous DMF and added under reflux for 3 hours. The reaction mixture was poured into saturated aqueous ammonium chloride solution and extracted with ethyl acetate. Wash the extract layer with saturated saline,
The extract was dried over magnesium sulfate and concentrated. The concentrate was applied to a silica gel column and poured out with a mixed solvent of hexane and ethyl acetate at a ratio of 5: 1 to give 2-t-butyl-1- (3-hydroxyphenyl) -1-methoxy-3-neopentyloxy-1. -Propene (compound [13]) 1.23
g, a yield of 59.5% was obtained as a colorless oil.

¹ HNMR (300 MHz, CDCl ₃ ); δ
0.92 (s, 9H), 1.26 (s, 9H), 2.83
(S, 2H), 3.25 (s, 3H), 3.58 (s, 2
H), 6.80 (ddd, J = 8.1, 2.6 and 1.0H
z, 1H), 6.90 (dd, J = 2.6 and 1.5Hz,
1H), 6.98 (d with fine coupling, J = 7.6H
z, 1H), 7.20 (dd, J = 8.1 and 7.6Hz,
1H) ppm IR (liquid film); 3400, 2960, 290
8, 2872, 1652, 1596, 1482 cm ^-1 Mass (m / z,%); 306 (M ⁺ , 25), 249 (5
6), 219 (60), 205 (39), 204 (62),
203 (34), 189 (36), 179 (47), 16
1 (29), 153 (29), 121 (100)

(Reference Example 6)

Embedded image

Compound [13] 411 synthesized in Reference Example 5
mg (1.34 mmol) was added to 5 ml of anhydrous toluene, and the mixture was stirred at 0 ° C under an argon atmosphere. To this solution 0.22 ml (1.58 mmol) triethylamine followed by 2-chloro-
1,3,2-dioxaphosphorane-2-oxide 0.12
5 ml (1.35 mmol) was added and the mixture was stirred at 0 ° C. for 30 minutes and then at room temperature for 2 hours. The reaction mixture was concentrated, ether was added, insoluble materials were filtered, and the filtrate was concentrated.
570 mg of a crude product of (2-t-butyl-1-methoxy-3-neopentyloxy-1-propen-1-yl) phenylethylene phosphate (compound [14]) was obtained as a colorless oil.

¹ HNMR (300 MHz, CDCl ₃ ); δ
0.93 (s, 9H), 1.26 (s, 9H), 2.84
(S, 2H), 3.25 (s, 3H), 3.56 (s, 2
H), 4.27 to 4.41 (m, 2H), 4.43 to 4.57
(M, 2H), 7.15 to 7.35 (m, 4H) ppm

(Reference Example 7)

[Chemical 31]

Compound [14] 570 synthesized in Reference Example 6
mg (1.38 mmol) was added to 5 ml of anhydrous DMF, and the mixture was stirred at room temperature under an argon atmosphere. To this solution was added sodium cyanide (95%) 69 mg (1.34 mmol), and the mixture was stirred overnight. The reaction mixture was concentrated, the concentrate was dissolved in hexane, extracted with water, and the extract layer was freeze-dried.
589 mg of a crude product of (2-t-butyl-1-methoxy-3-neopentyloxy-1-propen-1-yl) phenyl-2′-cyanoethyl phosphate (compound [15]) was obtained as an amorphous solid. Was given.

¹ HNMR (300 MHz, CD ₃ OD);
δ 0.95 (s, 9H), 1.31 (s, 9H), 2.81
(T, J = 6.3 Hz, 2H), 2.86 (s, 2H), 3.
29 (s, 3H), 3.68 (s, 2H), 4.15 (d
t, J = 7.7 and 6.3 Hz, 2H), 7.10-7.3
5 (m, 4H) ppm IR (KBr); 2958, 2868, 2260, 16
01, 1579, 1482, 1262, 1104 cm ^-1 Mass (FAB-pos, m / z,%); 485 ([M + H + N
a] ⁺ , 26), 484 ([M + Na] ⁺ , 100), 382
(24), 125 (55)

(Reference Example 8)

Embedded image

Compound [15] 485 synthesized in Reference Example 7
mg (1.05 mmol) was added to 2 ml of THF, and the mixture was stirred at room temperature under an argon atmosphere. To this solution were added 28% ammonia water (3.0 ml) and water (1.0 ml), and the mixture was stirred for 3 days. The reaction mixture was concentrated, the concentrate was dissolved in hexane and extracted with water. The extract layer was freeze-dried to give 460 mg of ammonium sodium 3- (2-t-butyl-1-methoxy-3-neopentyloxy-1-propen-1-yl) phenyl phosphate (Compound [16]), amorphous Obtained as a solid.

¹ HNMR (300 MHz, CD ₃ OD);
δ 0.94 (s, 9H), 1.31 (s, 9H), 2.85
(S, 2H), 3.29 (s, 3H), 3.69 (s, 2
H), 7.08 (d, J = 7.4Hz, 1H), 7.20
(S, 1H), 7.25 (dd, J = 7.4 and 8.0H
z, 1H), 7.35 (broad d, J = 8.0Hz, 1H) p
pm IR (KBr); 2958, 2866, 1598, 15
79, 1481, 1217, 1084 cm ^-1 Mass (FAB-pos, m / z,%); 431 ([M + H-N
H ₄ + Na] ⁺ , 48), 343 (30), 329
(35), 125 (100)

(Reference Example 9)

[Chemical 33]

69 mg of the compound [16] synthesized in Reference Example 8
(0.162 mmol) and 2 mg of TPP were dissolved in 15 ml of dichloromethane, and the mixture was stirred at 0 ° C under an oxygen atmosphere. This solution was irradiated with a Na lamp (180 W) for 2 hours. The reaction mixture was concentrated, applied to a silica gel column, and sequentially poured out using dichloromethane, a mixed solvent of dichloromethane and methanol in a ratio of 4: 1 and 2: 1.
-Butyl-4-methoxy-3-neopentyloxymethyl-4- (3'-phosphoryloxy) phenyl-1,2
23 mg of dioxetane ammonium sodium salt (Compound [17]) was obtained as an amorphous solid.

¹ HNMR (300 MHz, CD ₃ OD);
δ 0.73 (s, 9H), 1.33 (s, 9H), 2.25
(D, J = 8.2Hz, 1H), 2.64 (d, J = 8.2
Hz, 1H), 3.07 (s, 3H), 3.47 (d, J =
10.2Hz, 1H), 3.84 (d, J = 10.2Hz, 1
H), 7.13 to 7.55 (m, 4H) ppm

(Reference Example 10)

Embedded image

13 mg of the compound [17] synthesized in Reference Example 9
(0.028 mmol) was dissolved in 2.8 ml (0.028 mmol) of 0.01N aqueous sodium hydrogencarbonate solution and freeze-dried to give 3-t-butyl-4-methoxy-3-neopentyloxymethyl-. 13 mg of 4- (3'-phosphoryloxy) phenyl-1,2-dioxetane disodium salt (Compound [18]) was obtained as an amorphous solid.

¹ HNMR (300 MHz, CD ₃ OD);
δ 0.74 (s, 9H), 1.33 (s, 9H), 2.28
(D, J = 8.2Hz, 1H), 2.63 (d, J = 8.2
Hz, 1H), 3.06 (s, 3H), 3.44 (d, J =
10.2Hz, 1H), 3.84 (d, J = 10.2Hz, 1
H), 7.00 to 7.60 (m, 4H) ppm IR (KBr); 2960, 2872, 1590, 14
84, 1296, 1272, 1108, 992 cm ^-1 Mass (FAB-pos, m / z,%); 485 ([M + N
a] ⁺ , 21), 463 ([M + H] ⁺ , 38), 401
(26), 379 (14), 299 (52), 277 (7
3), 125 (43), 115 (100)

(Reference Example 11)

Embedded image

Compound [13] 168 synthesized in Reference Example 5
mg (0.549 mmol) was dissolved in 2 ml of DMF, and the mixture was stirred at room temperature under an argon atmosphere. Imidazole 6 in this solution
6 mg (0.969 mmol) and 100 mg (0.663 mmol) of t-butyldimethylchlorosilane were added, and the mixture was stirred for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate.
The extract layer was washed with saturated brine, dried over magnesium sulfate, and concentrated. The concentrate was applied to a silica gel column and poured out with a mixed solvent of hexane and ethyl acetate of 20: 1,
2-t-butyl-1- [3- (t-butyldimethylsiloxy) phenyl] -1-methoxy-3-neopentyloxy-1-propene (Compound [19]) was 158 mg in a yield of 68.5%. Obtained as a colorless oil.

¹ HNMR (90 MHz, CDCl ₃ ); δ
0.19 (s, 6H), 0.90 (s, 9H), 0.98
(S, 9H), 1.26 (s, 9H), 2.81 (s, 2
H), 2.33 (s, 3H), 3.62 (s, 2H), 6.7
3 to 6.87 (m, 2H), 6.97 to 7.03 (m, 1
H), 7.14 to 7.19 (m, 1H) ppm

(Reference Example 12)

Embedded image

Compound [19] 50 synthesized in Reference Example 11
mg (0.119 mmol) and 5 mg of TPP were dissolved in 10 ml of dichloromethane, and the mixture was stirred at -78 ° C under an oxygen atmosphere. This solution was irradiated with a Na lamp (940 W) for 2 hours. The reaction mixture was concentrated, applied to a silica gel column, and poured out with a mixed solvent of hexane and ethyl acetate of 20: 1. 3-t-butyl-4- [3- (t-butyldimethylsiloxy) phenyl] -4-methoxy -3-Neopentyloxymethyl-1,2-dioxetane (Compound [20]) was obtained as a colorless oily substance in 35 mg, yield 65%.

¹ HNMR (90 MHz, CDCl ₃ ); δ
0.20 (s, 6H), 0.68 (s, 9H), 0.99
(S, 9H), 1.29 (s, 9H), 2.38 (q _AB , J
= 8.4 Hz, 2 H), 3.04 (s, 3 H), 3.63 (q
_AB , J = 10.0Hz, 2H), 6.78-6.89 (m,
1H), 7.00 to 7.24 (m, 3H) ppm IR (liquid film); 2960, 1600, 148
0,1280,1100,920,840 cm ^-1

(Reference Example 13)

Embedded image

25.0 ml of diisopropylamine (0.17)
(8 mol) was added to 200 ml of anhydrous THF at room temperature under an argon atmosphere, and butyllithium (1.62M) was added to the stirred solution.
110 ml (0.178 mol) of a hexane solution) was added, and the mixture was stirred for 1 hour. This solution was cooled to −78 ° C., 30.0 ml (0.178 mol) of ethyl t-butyl acetate was added, and the mixture was stirred for 30 minutes, and subsequently, 21.0 g of methyl 3-benzyloxybenzoate (Compound [21]) ( (86.8 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into 1N hydrochloric acid and extracted with ethyl acetate. The extract layer was washed with saturated brine, dried over magnesium sulfate, and concentrated. The concentrate was applied to a silica gel column and was poured out with a mixed solvent of hexane and ethyl acetate of 9: 1. Ethyl 2- (3-benzyloxybenzoyl) -2-t-butyl acetate (compound [2
2]) was obtained with a yield of 28.31 g and a yield of 92.2%.

Mp: 53.5-54.0 ° C. (colorless fine-grained crystals, recrystallized from methanol) ¹ HNMR (300 MHz, CDCl ₃ ); δ1.14
(S, 9H), 1.18 (t, J = 7.1Hz, 3H), 4.
13 (q, J = 7.1Hz, 2H), 4.26 (s, 1
H), 5.11 (s, 2H), 7.18 (d with fine coup
ling, J = 8.2 Hz, 1 H), 7.32 to 7.48 (m,
6H), 7.52 to 7.59 (m, 2H) ppm IR (KBr); 2964, 1728, 1696, 15
92 cm ^-1 Mass (m / z,%); 354 (M ⁺ , 19), 298 (1
8), 211 (39), 91 (100)

(Embodiment 7)

[Chemical 38]

Compound [22] 2 synthesized in Reference Example 13
8.1 g (79.4 mmol) was added to 200 ml of anhydrous DMSO, and 20.1 g (0.179 mol) of potassium t-butoxide was added to the solution stirred at room temperature under a nitrogen atmosphere and stirred for 15 minutes. The solution was cooled to 0 ° C and dimethylsulfate 15.
0 ml (0.158 mol) was added dropwise over 15 minutes, and the mixture was stirred at room temperature for 30 minutes. The solution was cooled to 0 ° C and t-
7.30 g (65.1 mmol) of butoxypotassium and then 5.4 ml (56.9 mmol) of dimethylsulfate were added in 2 portions and 4
Stir for 30 minutes at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The extract layer was washed with saturated brine, dried over magnesium sulfate, and concentrated. The concentrate was applied to a silica gel column and poured out with a mixed solvent of hexane and ethyl acetate at a ratio of 10: 1 to give ethyl 3- (3-benzyloxyphenyl) -2-t-butyl-3-methoxy-2-propenoate ( Compound [23]) 24.9 g, yield 85.2
% As a colorless oil.

¹ HNMR (300 MHz, CDCl ₃ ); δ
0.90 (t, J = 7.1Hz, 3H), 1.29 (s, 9
H), 3.30 (s, 3H), 3.85 (q, J = 7.1H
z, 2H), 5.06 (s, 2H), 6.90 to 7.01
(M, 3H), 7.22 (t, J = 7.8Hz, 1H), 7.
28-7.47 (m, 5H) ppm IR (liquid film); 2960, 1718, 163
6,1596,1580 cm ^-1 Mass (m / z,%); 368 (M ⁺ , 59), 354 (2
5), 353 (100), 91 (83)

(Embodiment 8)

[Chemical Formula 39]

Compound [23] synthesized in Example 7 19.
63 g (53.3 mmol) was added to 150 ml of anhydrous toluene, and the mixture was stirred at -78 ° C under an argon atmosphere. 70.0 ml (0.123 mol) of diisobutylaluminum hydride (25% toluene solution) was added to this solution, and the mixture was stirred for 45 minutes. 7.0 ml (12.3 mmol) of diisobutylaluminum hydride (25% toluene solution) was further added to this solution, and the mixture was stirred for 2 hours. The reaction mixture was poured into 1N hydrochloric acid and extracted with ethyl acetate. The extract layer was washed with saturated brine, dried over magnesium sulfate, and concentrated. The concentrate was crystallized with a mixed solvent of hexane and ethyl acetate to give 3- (3-benzyloxyphenyl) -2-t-butyl-3-methoxy-2.
-Propen-1-ol (compound [24]) was 8.70
g, yield 50.0%. The filtrate was concentrated, applied to a silica gel column and poured out with a mixed solvent of hexane and ethyl acetate at a ratio of 4: 1.
g, yield 39.1%.

Mp: 59.5-60.0 ° C. (colorless granular crystals,
Recrystallized from hexane and ethyl acetate) ¹ HNMR (300 MHz, CDCl ₃ ); δ 0.94
(T, J = 5.4Hz, 1H), 1.31 (s, 9H), 3.
23 (s, 3H), 3.92 (d, J = 5.4Hz, 2
H), 5.09 (s, 2H), 6.90 to 7.00 (m, 3
H), 7.25 to 7.47 (m, 6H) ppm IR (KBr); 3464, 2956, 1634, 15
88 cm ^-1 Mass (m / z,%); 326 (M ⁺ , 46), 311 (4
3), 269 (39), 91 (100)

(Example 9)

[Chemical 40]

Compound [24] 772 synthesized in Example 8
mg (2.37 mmol) to 2.0 ml of 1-bromoundecane
(8.96 mmol), and the mixture was stirred at room temperature under an argon atmosphere. 50% aqueous sodium hydroxide solution 2.
0 ml (25.0 mmol) and tetrabutylammonium bromide 89 mg (0.276 mmol) were added, and the mixture was heated with stirring at 80 ° C. for 3 hours. To this solution was further added 99 mg (0.307 mmol) of tetrabutylammonium bromide, and the mixture was heated with stirring for 3 hours and 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The extract layer was washed with saturated brine, dried over magnesium sulfate, and concentrated. The concentrate was applied to a silica gel column and poured out with a mixed solvent of hexane and ethyl acetate of 10: 1, and 1- (3-benzyloxyphenyl) -2-t-butyl-1-methoxy-3-undecanoxy-1-propene was obtained. (Compound [25]) was obtained as a colorless oil in a yield of 39.4% (448 mg).

¹ HNMR (300 MHz, CDCl ₃ ); δ
0.84 to 0.92 (m, 3H), 1.20 to 1.36
(M, 16H), 1.28 (s, 9H), 1.44 to 1.5
6 (m, 2H), 3.20 (t, J = 6.6Hz, 2H),
3.23 (s, 3H), 3.67 (s, 2H), 5.07
(S, 2H), 6.95 (d with fine coupling, J =
8.2Hz, 1H), 6.99 (d, J = 7.6Hz, 1
H), 7.05 (s with fine coupling, 1H), 7.2
5 (dd, J = 8.2 and 7.6 Hz, 1 H), 7.28-
7.48 (m, 5H) ppm IR (liquid film); 2928, 2856, 163
6,1596,1580 cm ^-1 Mass (m / z,%); 480 (M ⁺ , 28), 424 (3
1), 423 (100), 333 (19), 309 (1
6), 91 (67)

(Reference Example 14)

Embedded image

Compound [25] 718 synthesized in Example 9
mg (1.50 mmol) and 10% Pd-C 125 mg were added to a mixed solvent of ethyl acetate 7 ml and methanol 2 ml, and the mixture was stirred under a hydrogen atmosphere at room temperature for 2 hours. The reaction mixture was filtered through Celite and concentrated. The concentrate was applied to a silica gel column and poured out with a mixed solvent of hexane and ethyl acetate at a ratio of 5: 1 to give 2-t-butyl-1- (3-hydroxyphenyl) -1-methoxy-3-undecanoxy-1-propene. (Compound [26]) 528 mg, yield 90.5%
And was obtained as a colorless oil.

¹ HNMR (300 MHz, CDCl ₃ ); δ
0.84 to 0.92 (m, 3H), 1.18 to 1.35
(M, 16H), 1.27 (s, 9H), 1.43 to 1.5
9 (m, 2H), 3.21 (t, J = 6.5Hz, 2H),
3.24 (s, 3H), 3.66 (s, 2H), 6.80
(Ddd, J = 8.0, 2.6 and 0.8Hz, 1H),
6.86 (s with fine coupling, 1H), 6.95 (d
with fine coupling, J = 7.6Hz, 1H), 7.21
(Dd, J = 8.0 and 7.6Hz, 1H) ppm IR (liquid film); 3384, 2928, 285
6, 1636, 1596, 1584 cm ^-1 Mass (m / z,%); 390 (M ⁺ , 16), 334 (2
3), 333 (100), 219 (17), 203 (3
2), 179 (22), 161 (20)

(Reference Example 15)

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Compound [26] 84 synthesized in Reference Example 14
mg (0.215 mmol) was dissolved in DMF (1.5 ml), and the mixture was stirred at room temperature under argon atmosphere. To this solution, 30 mg (0.441 mmol) of imidazole and 60 mg (0.398 mmol) of t-butyldimethylchlorosilane were added and stirred for 2 hours. To this solution was further added 18 mg of imidazole (0.2
64 mmol) and t-butyldimethylchlorosilane 36
mg (0.239 mmol) was added and the mixture was stirred for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The extract layer was washed with saturated brine, dried over magnesium sulfate, and concentrated. The concentrate was applied to a silica gel column, and hexane and ethyl acetate were added.
When it was poured out with a mixed solvent of 0: 1, 2-t-butyl-
1- [3- (t-butyldimethylsiloxy) phenyl]
-1-Methoxy-3-undecanoxy-1-propene (Compound [27]) was obtained as a colorless oily substance in 100 mg, yield 92.1%.

¹ HNMR (300 MHz, CDCl ₃ ); δ
0.19 (s, 6H), 0.84 to 0.92 (m, 3H),
0.99 (s, 9H), 1.18 to 1.35 (m, 16
H), 1.28 (s, 9H), 1.42 to 1.53 (m, 2
H), 3.17 (t, J = 6.6Hz, 2H), 3.23
(S, 3H), 3.68 (s, 2H), 6.80 (ddd,
J = 8.1, 2.5 and 0.9Hz, 1H), 6.84 (s)
with fine coupling, 1H), 6.96 (d with fine co
upling, J = 7.6Hz, 1H), 7.18 (dd, J =
8.1 and 7.6Hz, 1H) ppm

(Example 16)

[Chemical 43]

Compound [27] 60 synthesized in Reference Example 15
mg (0.119 mmol) and 5 mg of TPP were dissolved in 20 ml of dichloromethane, and the mixture was stirred at 0 ° C. under an oxygen atmosphere. This solution was irradiated with a Na lamp (180 W) for 3 hours. The reaction mixture was concentrated, subjected to preparative TLC, developed with a 20: 1 mixed solvent of hexane and benzene to give 3-t-butyl-4- [3- (t-butyldimethylsiloxy) phenyl] -4-methoxy-. 3-Undecanoxymethyl-
38 mg of 1,2-dioxetane (compound [28]) was isolated in a yield of 59.6% as a colorless oil.

¹ HNMR (300 MHz, CDCl ₃ ); δ
0.20 (s, 6H), 0.84 to 0.92 (m, 3H),
0.99 (s, 9H), 1.02 to 1.35 (m, 18
H), 1.28 (s, 9H), 2.47 (dt, J = 9.0)
and 6.2 Hz, 1 H), 2.87 (dt, J = 9.0 and
6.4 Hz, 1 H), 3.03 (s, 3 H), 3.50 (d,
J = 10.1Hz, 1H), 3.72 (d, J = 10.1H)
z, 1H), 6.84 (ddd, J = 8.0, 2.4 and 1.
0Hz, 1H), 6.90 to 7.18 (m, 2H), 7.24
(T, J = 8.0Hz, 1H) ppm

(Embodiment 10)

[Chemical 44]

Compound [11] 1.1 synthesized in Example 5
64 g (4.66 mmol) was added to 12 ml of anhydrous DMF, and the mixture was stirred at room temperature under an argon atmosphere. To this solution, 340 mg (8.50 mmol) of 60% sodium hydride and 0.83 ml (6.98 mmol) of benzyl bromide were added, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The extract layer was washed with saturated brine, dried over magnesium sulfate, and concentrated. The concentrate was applied to a silica gel column and poured out with a 20: 1 mixed solvent of hexane and ethyl acetate to give 3-benzyloxy-2-t-butyl-
1.099 g of 1-methoxy-1- (3-methoxyphenyl) -1-propene (compound [29]), yield 69.4.
% As a colorless oil.

¹ HNMR (300 MHz, CDCl ₃ ); δ
1.30 (s, 9H), 3.25 (s, 3H), 3.76
(S, 2H), 3.78 (s, 3H), 4.31 (s, 2)
H), 6.87 (ddd, J = 8.2, 2.6 and 1.1H
z, 1H), 6.93 to 7.00 (m, 2H), 7.19 to
7.39 (m, 6H) ppm IR (liquid film); 2956, 1634, 159
6, 1580 cm ^-1 Mass (m / z,%); 340 (M ⁺ , 36), 283 (3
0), 234 (75), 233 (29), 219 (32),
217 (46), 203 (23), 193 (100), 1
87 (24), 177 (67), 91 (88)

(Reference Example 17)

Embedded image

Compound [29] 48 synthesized in Example 10
7 mg (1.43 mmol) and 60% sodium hydride 1
50 mg (3.75 mmol) was added to 6 ml of DMF, and the mixture was stirred at 0 ° C under an argon atmosphere. 0.23 ml (3.11 mmol) of ethanethiol was added to this solution, and the mixture was stirred for 10 minutes and then heated and stirred at 120 ° C. for 2 hours. The reaction solution was poured into saturated saline and extracted with ethyl acetate. The extract layer was washed with saturated brine, dried over magnesium sulfate, and concentrated. The concentrate was applied to a silica gel column and hexane and ethyl acetate were added to 5:
When it was poured out with a mixed solvent of 1, 3-benzyloxy-2-t-butyl-1- (3-hydroxyphenyl)-
1-methoxy-1-propene (compound [30]) is 21
8 mg, yield 46.7%.

Mp: 93.0-94.0 ° C (colorless granular crystals,
Recrystallized from hexane) ¹ HNMR (300 MHz, CDCl ₃ ); δ 1.29
(S, 9H), 3.24 (s, 3H), 3.76 (s, 2
H), 4.32 (s, 2H), 4.72 (s, 1H), 6.7
9 (ddd, J = 8.1, 2.5 and 0.7Hz, 1H),
6.85 (broad s, 1H), 6.94 (d with finecou
pling, J = 7.7 Hz, 1 H), 7.19 (dd, J = 8.
1 and 7.7Hz, 1H), 7.20 to 7.35 (m, 5
H) ppm IR (KBr); 3272, 2956, 2908, 16
38,1594 cm ^-1 Mass (m / z,%); 326 (M ⁺ , 36), 269 (3
2), 220 (76), 219 (27), 205 (33),
203 (60), 179 (82), 163 (68), 16
1 (36), 91 (100)

(Reference Example 18)

Embedded image

Compound [30] 12 synthesized in Reference Example 17
7 mg (0.390 mmol) was dissolved in 2 ml of anhydrous DMF and stirred at room temperature under argon atmosphere. 55 mg (0.808 mmol) of imidazole and 85 mg (0.564 mmol) of t-butyldimethylchlorosilane were added to this solution, and the mixture was stirred overnight. The reaction solution was poured into water and extracted with ethyl acetate.
The extract layer was washed with saturated brine, dried over magnesium sulfate, and concentrated. The concentrate was applied to a silica gel column and poured out with a mixed solvent of hexane and ethyl acetate of 100: 1, and 3-benzyloxy-2-t-butyl-1- [3-
(T-Butyldimethylsiloxy) phenyl] -1-methoxy-1-propene (Compound [31]) was obtained as a colorless oily substance in 144 mg, yield 84.0%.

¹ HNMR (300 MHz, CDCl ₃ ); δ
0.17 (s, 6H), 0.97 (s, 9H), 1.29
(S, 9H), 3.23 (s, 3H), 3.77 (s, 2
H), 4.29 (s, 2H), 6.80 (ddd, J = 8.
0, 2.5 and 1.0Hz, 1H), 6.85 (s with fi
ne coupling, 1H), 6.97 (d with fine couplin
g, J = 7.6 Hz, 1 H), 7.18 (dd, J = 8.0 a
nd 7.6Hz, 1H), 7.17 to 7.35 (m, 5H) pp
m IR (liquid film); 2956, 2936, 163
4, 1598, 1580, 1262 cm ^-1 Mass (m / z,%); 440 (M ⁺ , 22), 383 (1
9), 335 (28), 334 (100), 333 (2
9), 293 (52), 277 (42), 235 (13),
91 (65)

(Reference Example 19)

[Chemical 47]

Compound [31] 49 synthesized in Reference Example 18
mg (0.111 mmol) and TPP 4 mg were added to dichloromethane 20 ml, and the mixture was stirred at 0 ° C. under oxygen atmosphere. This solution was irradiated with a Na lamp (180 W) for 4 hours. The reaction mixture was concentrated, applied to a silica gel column, and poured out with a mixed solvent of hexane and ethyl acetate at a ratio of 200: 1. 3-benzyloxymethyl-3-t-butyl-4- [3- (t-butyldimethylsiloxy) ) Phenyl] -4-methoxy-1,2-dioxetane (Compound [32]) was obtained as a colorless oil in 42 mg, yield 79.9%.

¹ HNMR (300 MHz, CDCl ₃ ); δ
0.17 (broad s, 6H), 0.98 (s, 9H), 1.
29 (s, 9H), 3.05 (s, 3H), 3.57 (d,
J = 10.2Hz, 1H), 3.71 (d, J = 11.5H
z, 1H), 3.84 (d, J = 10.2Hz, 1H), 3.
84 (d, J = 11.5 Hz, 1 H), 6.83 to 6.90
(M, 1H), 6.95 to 7.30 (m, 8H) ppm IR (liquid film); 2960, 2936, 160
2,1586,1256,1096 cm ^-1 Mass (m / z,%); 472 (M ⁺ , trace), 440
(2), 266 (26), 210 (22), 209 (10
0), 177 (20), 149 (11), 91 (41)

(Embodiment 11)

Embedded image

Compound synthesized in Reference Example 4

[9] 4.00
g (14.4 mmol) was added to 30 ml of anhydrous DMSO, and 3.26 g (29.1 mmol) of potassium t-butoxide was added to the solution stirred at room temperature under an argon atmosphere and stirred for 15 minutes. 2.7 ml of isopropyl bromide (28.
8 mmol) was added and the mixture was stirred for 4 hours. To this solution, 11.02 g (98.2 mmol) of potassium t-butoxide and 9.3 ml (99.0 mmol) of isopropyl bromide were added in 5 portions over 24 hours. The reaction mixture was poured into saturated saline and extracted with ethyl acetate. Wash the extract layer with saturated saline,
The extract was dried over magnesium sulfate and concentrated. The concentrate was applied to a silica gel column and poured out with a mixed solvent of hexane and ethyl acetate of 9: 1, and ethyl 2-t-butyl-3-isopropoxy-3- (3-methoxyphenyl) -2-propenoate ( Compound [33]) 3.73 g, yield 81.0
% As a colorless oil.

¹ HNMR (300 MHz, CDCl ₃ ); δ
0.86 (t, J = 7.1Hz, 3H), 1.15 (d, J
= 6.2 Hz, 6 H), 1.30 (s, 9 H), 3.79
(S, 3H), 3.79 (q, J = 7.1Hz, 2H), 3.
87 (hept, J = 6.2 Hz, 1 H), 6.83 (ddd,
J = 8.2, 2.6 and 0.8 Hz, 1 H), 6.87 (sw)
ith fine coupling, 1H), 6.91 (dd, J = 7.5)
and 0.9Hz, 1H), 7.21 (dd, J = 8.2 and
7.5Hz, 1H) ppm IR (liquid film); 2976, 1718, 163
2,1598,1580 cm ^-1 Mass (m / z,%); 320 (37), 275 (12), 2
63 (15), 233 (24), 232 (94), 217
(55), 176 (20), 135 (100)

(Example 12)

[Chemical 49]

Compound [33] synthesized in Example 11.3.
72 g (11.6 mmol) was added to 35 ml anhydrous toluene,
The mixture was stirred at -78 ° C under an argon atmosphere. Diisobutylaluminum hydride (25% hexane solution) was added to this solution.
15.0 ml (26.4 mmol) was added and the mixture was stirred for 4 hours. The reaction mixture was poured into a mixed solution of water and ethyl acetate stirred at 0 ° C., stirred for 20 minutes, and then filtered through Celite. The organic layer was separated, washed with saturated brine, dried over magnesium sulfate, and concentrated. The concentrate was applied to a silica gel column and was poured out with a mixed solvent of hexane and ethyl acetate at a ratio of 4: 1.
-Butyl-3-isopropoxy-3- (3-methoxyphenyl) -2-propen-1-ol (compound [3
4]) was obtained as a colorless oil in a yield of 7.47 g and a yield of 76.4%.

¹ HNMR (300 MHz, CDCl ₃ ); δ
0.89 (t, J = 5.6Hz, 1H), 1.12 (d, J
= 6.2 Hz, 6 H), 1.33 (s, 9 H), 3.75 (he
pt, J = 6.2 Hz, 1 H), 3.82 (s, 3 H), 3.8
9 (d, J = 5.6 Hz, 2 H), 6.82 to 6.92
(M, 3H), 7.23 to 7.31 (m, 1H) ppm IR (liquid film); 3460, 2976, 162
8, 1598, 1580 cm ^-1 Mass (m / z,%); 278 (M ⁺ , 31), 261 (2
0), 219 (46), 218 (24), 203 (54),
135 (100), 107 (20)

(Reference Example 13)

Embedded image

Compound [34] synthesized in Example 12 1.
195 g (4.30 mmol) was added to 12 ml anhydrous DMF,
The mixture was stirred at room temperature under an argon atmosphere. 60% in this solution
325 mg (8.13 mmol) of sodium hydride and 1.20 ml (9.53 mmol) of neopentyl bromide were added to 1
The mixture was heated and stirred at 00 ° C for 1 hour. Throw the reaction mixture in water,
It was extracted with ethyl acetate. The extract layer was washed with saturated brine, dried over magnesium sulfate, and concentrated. The concentrate was applied to a silica gel column and poured out with a mixed solvent of hexane and ethyl acetate at a ratio of 20: 1. 2-t-butyl-1-isopropoxy-1- (3-methoxyphenyl) -3-neopentyloxy- 1-propene (compound [35]) is 1.1
It was obtained as a colorless oil in 94 g, yield 79.8%.

¹ HNMR (300 MHz, CDCl ₃ ); δ
0.88 (s, 9H), 1.12 (d, J = 6.2Hz, 6
H), 1.29 (s, 9H), 2.76 (s, 2H), 3.5
6 (s, 2H), 3.77 (hept, J = 6.2Hz, 1
H), 3.80 (s, 3H), 6.84 (ddd, J = 8.
0, 2.7 and 1.0Hz, 1H), 6.87 (s with fin
e coupling, 1H), 6.94 (d with fine couplin
g, J = 7.5Hz, 1H), 7.22 (dd with fine cou
pling, J = 8.0 and 7.5 Hz, 1 H) ppm IR (liquid film); 2956, 2868, 163
2, 1598, 1580 cm ^-1 Mass (m / z,%); 348 (M ⁺ , 50), 291 (4
0), 261 (18), 219 (43), 218 (23),
203 (75), 179 (27), 135 (100), 1
07 (18)

(Reference Example 20)

[Chemical 51]

60% sodium hydride 389 mg (9.7
3 mmol) in 15 ml of anhydrous DMF under argon atmosphere at 0
0.8 ml (10.8) of ethanethiol was added to the solution suspended at ℃.
mmol) was added and stirred for 20 minutes. Example 13 was added to this solution.
1.52 g (4.37 mmol) of the compound [35] synthesized in 1.
Was dissolved in 10 ml of anhydrous DMF and added, and the mixture was heated with stirring at 120 ° C. for 6 hours. The reaction mixture was poured into saturated saline and extracted with ethyl acetate. The extract layer was washed with saturated brine, dried over magnesium sulfate, and concentrated. The concentrate is applied to a silica gel column, hexane and ethyl acetate 10: 1, then 4: 1.
When poured out with a mixed solvent of 2-t-butyl-1-
(3-Hydroxyphenyl) -1-isopropoxy-3
-Neopentyloxy-1-propene (compound [3
6]) was obtained as a pale yellow oil in a yield of 1.208 g and a yield of 82.7%.

¹ HNMR (300 MHz, CDCl ₃ ); δ
0.90 (s, 9H), 1.12 (d, J = 6.1Hz, 6
H), 1.27 (s, 9H), 2.76 (s, 2H), 3.5
3 (s, 2H), 3.79 (hept, J = 6.1Hz, 1
H), 4.65 (s, 1H), 6.78 (ddd, J = 8.
1,2.6 and 0.9Hz, 1H), 6.84 (s with fin
e coupling, 1H), 6.92 (d with fine couplin
g, J = 7.6 Hz, 1 H), 7.18 (dd, J = 8.1 a
nd 7.6Hz, 1H) ppm IR (liquid film); 3400, 2960, 287
2, 1628 cm ^-1 Mass (m / z,%); 334 (M ⁺ , 41), 277 (3
5), 247 (23), 205 (55), 204 (37),
189 (72), 165 (26), 121 (100), 9
3 (16)

(Reference Example 21)

Embedded image

Compound [36] 12 synthesized in Reference Example 20
2 mg (0.365 mmol) was dissolved in 2 ml of anhydrous DMF and stirred at room temperature under argon atmosphere. To this solution, 0.15 ml (1.08 mmol) of triethylamine and 110 mg (0.730 mmol) of t-butyldimethylchlorosilane were added and stirred overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The extract layer was washed with saturated brine, dried over magnesium sulfate, and concentrated. The concentrate was applied to a silica gel column and poured out with a mixed solvent of hexane and ethyl acetate at a ratio of 25: 1. 2-t-butyl-1- [3- (t-butyldimethylsiloxy) phenyl] -1-isopropoxy- 3-neopentyloxy-1-propene (compound [3
7]) was obtained as a colorless oily substance in a yield of 121 mg and 73.9%.

¹ HNMR (300 MHz, CDCl ₃ ); δ
0.18 (s, 6H), 0.87 (s, 9H), 0.98
(S, 9H), 1.11 (d, J = 6.2Hz, 6H), 1.
28 (s, 9H), 2.75 (s, 2H), 3.58 (s,
2H), 3.74 (hept, J = 6.2Hz, 1H), 6.75
~ 6.82 (m, 2H), 6.93 (d with fine coupli
ng, J = 7.6 Hz, 1 H), 7.15 (dd, J = 7.6)
and 7.4Hz, 1H) ppm IR (liquid film); 2956, 2864, 163
0, 1596, 1578, 1260, 1086 cm ^-1 Mass (m / z,%); 448 (M ⁺ , 100), 391 (7)
0), 361 (26), 319 (56), 318 (25),
303 (52), 279 (30), 261 (74), 23
5 (45)

(Reference Example 22)

Embedded image

Compound [37] 68 synthesized in Reference Example 21
mg (0.152 mmol) and 4 mg of TPP were dissolved in 20 ml of dichloromethane, and the mixture was stirred at 0 ° C under an oxygen atmosphere. The solution was irradiated with a Na lamp (180 W) for 2 hours. The reaction mixture was concentrated, applied to a silica gel column, and poured out with a mixed solvent of hexane and ethyl acetate of 100: 1. 3-t-butyl-4- [3- (t-butyldimethylsiloxy) phenyl] -4- Isopropoxy-3
-Neopentyloxymethyl-1,2-dioxetane (compound [38]) was obtained as a colorless oily substance with a yield of 52 mg and a yield of 71.4%.

¹ HNMR (300 MHz, CDCl ₃ ); δ
0.21 (broad s, 6H), 0.72 (s, 9H), 0.
90-1.10 (m, 12H), 1.15-1.30 (m,
3H), 1.32 (s, 9H), 2.10 to 2.24 (m,
1H), 2.56 (d, J = 8.3Hz.1H), 3.32
(D, J = 10, 1 Hz, 1 H), 3.40 to 3.64
(M, 2H), 6.70 to 6.96 (m, 2H), 7.14
~ 7.40 (m, 2H) ppm IR (liquid film); 2960, 2936, 286
8,1602,1586,1256,1100 cm ^-1 Mass (m / z,%); 448 (M ⁺ -32,7), 294.
(45), 238 (25), 237 (67), 235 (2
5), 196 (36), 195 (100), 167 (1
9), 135 (21), 71 (54), 57 (70)

(Example 14)

[Chemical 54]

Compound [24] 652 synthesized in Example 8
mg (2.00 mmol) and 2- (2-methoxyethoxy) ethyl bromide 0.55 ml (4.0 mmol) in TH
It was dissolved in F4 ml and stirred at room temperature under an argon atmosphere.
408 mg (10.2 mmol) of sodium hydroxide was added to this solution,
67 mg of tetrabutylammonium bromide (0.20
(8 mmol) and 0.1 ml of water were added, and the mixture was heated under reflux for 8 hours and 40 minutes. To this solution was further added 0.60 ml (4.42 mmol) of 2- (2-methoxyethoxy) ethyl bromide, 530 mg (13.3 mmol) of sodium hydroxide and 69 mg (0.214 mmol) of tetrabutylammonium bromide.
Was added and the mixture was heated under reflux overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The extract layer was washed with saturated brine, dried over magnesium sulfate, and concentrated. The concentrate was applied to a silica gel column and was poured out with a mixed solvent of hexane and ethyl acetate at a ratio of 4: 1. 1- (3-benzyloxyphenyl)-
2-t-butyl-1-methoxy-3- [2- (2-methoxyethoxy) ethoxy] -1-propene (compound [3
9]) was obtained as a colorless oil in a yield of 69.0% (591 mg).

¹ HNMR (300 MHz, CDCl ₃ ); δ
1.28 (s, 9H), 3.22 (s, 3H), 3.34
(S, 3H), 3.37 to 3.42 (m, 2H), 3.46
~ 3.51 (m, 2H), 3.54 to 3.61 (m, 4
H), 3.77 (s, 2H), 5.07 (s, 2H), 6.9
2 to 7.02 (m, 3H), 7.22 to 7.48 (m, 6
H) ppm IR (liquid film); 2876, 1636, 159
6,1580 cm ^-1 Mass (m / z,%); 428 (M ⁺ , 49), 371 (1
0), 309 (16), 308 (13), 293 (26),
251 (67), 217 (29), 91 (100)

(Reference Example 23)

[Chemical 55]

Compound [39] 45 synthesized in Example 14
1 mg (1.05 mmol) and 10% Pd-C, 54 mg were added to 7 ml of a 5: 2 mixed solvent of ethyl acetate and methanol,
The mixture was stirred under a hydrogen atmosphere at room temperature for 2.5 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated. The concentrate was applied to a silica gel column and poured out with a 2: 1 mixed solvent of hexane and ethyl acetate, and 2-t-butyl-1- (3-
Hydroxyphenyl) -1-methoxy-3- [2- (2
-Methoxyethoxy) ethoxy] -1-propene (Compound [40]) was obtained as a colorless oil in a yield of 84.2% (300 mg).

¹ HNMR (300 MHz, CDCl ₃ ); δ
1.26 (s, 9H), 3.29 (s, 3H), 3.40 ~
3.46 (m, 2H), 3.44 (s, 3H), 3.62
(S, 2H), 3.60 to 3.74 (m, 6H), 6.80
~ 6.87 (m, 2H), 7.18 ~ 7.25 (m, 2H)
ppm IR (liquid film); 3380, 2956, 292
8, 2876, 1634, 1596, 1582 cm ^-1 Mass (m / z,%); 338 (M ⁺ , 77), 281 (3
3), 219 (30), 218 (23), 203 (73),
161 (100), 103 (36), 59 (31)

(Reference Example 24)

[Chemical 56]

Compound [40] 13 synthesized in Reference Example 23
5 mg (0.399 mmol) was dissolved in 2 ml of anhydrous DMF and stirred at room temperature under an argon atmosphere. To this solution, 0.11 ml (0.789 mmol) of triethylamine and 78 mg (0.518 mmol) of t-butyldimethylchlorosilane were added, and the mixture was stirred for 1.5 hours. To this solution was further added 0.10 ml (0.717 mmol) of triethylamine and 58 mg (0.385 mmol) of t-butyldimethylchlorosilane,
Stir for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The extract layer was washed with saturated brine, dried over magnesium sulfate, and concentrated. The concentrate was applied to a silica gel column and poured out with a mixed solvent of hexane and ethyl acetate at a ratio of 4: 1. 2-t-butyl-1- [3- (t-butyldimethylsiloxy) phenyl] -1-methoxy-3 -[2-
(2-Methoxyethoxy) ethoxy] -1-propene (Compound [41]) was obtained as a colorless oil in a yield of 173 mg and a yield of 95.8%.

¹ HNMR (300 MHz, CDCl ₃ ); δ
0.19 (s, 6H), 0.99 (s, 9H), 1.28
(S, 9H), 3.22 (s, 3H), 3.37 (s, 3
H), 3.34 to 3.40 (m, 2H), 3.49 to 3.62
(M, 6H), 3.78 (s, 2H), 6.77 to 6.83
(M, 2H), 6.95 (d with fine coupling, J =
7.6 Hz, 1 H), 7.19 (dd, J = 8.7 and 7.
6Hz, 1H) ppm IR (liquid film); 2956, 2936, 286
4, 1636, 1596, 1578 cm ^-1 Mass (m / z,%); 452 (M ⁺ , 55), 395 (1
1), 333 (27), 317 (45), 376 (29),
275 (100)

(Reference Example 25)

[Chemical 57]

Compound [41] 54 synthesized in Reference Example 24
mg (0.119 mmol) and 10 mg of TPP were dissolved in 20 ml of dichloromethane, and the mixture was stirred at 0 ° C. under an oxygen atmosphere.
This solution was irradiated with a Na lamp (180 W) for 8 hours. The reaction solution was concentrated and applied to a silica gel column, followed by dichloromethane, followed by dichloromethane and ethyl acetate.
When it was made to flow out with a mixed solvent of 5: 1, 3-t-butyl-4- [3- (t-butyldimethylsiloxy) phenyl] -4-methoxy-3- [2- (2-methoxyethoxy) ethoxymethyl ] -1,2-Dioxetane (Compound [42]) was obtained as a pale yellow oily substance in 38 mg in a yield of 65.7%.

¹ HNMR (300 MHz, CDCl ₃ ); δ
0.20 (s, 6H), 0.99 (s, 9H), 1.28
(S, 9H), 2.66 to 2.77 (m, 1H), 2.99
~ 3.10 (m, 1H), 3.04 (s, 3H), 3.20
~ 3.32 (m, 2H), 3.35 (s, 3H), 3.40
~ 3.52 (m, 4H), 3.61 (d, J = 10.3H
z, 1H), 3.77 (d with fine coupling, J = 10.
3Hz, 1H), 6.81 to 6.87 (m, 1H), 6.92
~ 7.30 (m, 3H) ppm IR (liquid film); 2936, 2888, 160
4,1586,1256,1104 cm ^-1 Mass (m / z,%); 452 (M ⁺ -32,1), 266
(27), 210 (22), 209 (100), 177
(19)

(Example 15)

Embedded image

Compound [11] 960 synthesized in Example 5
mg (3.84 mmol) was dissolved in 10 ml of anhydrous DMF and stirred at room temperature under argon atmosphere. To this solution, 330 mg (8.25 mmol) of 60% sodium hydride and 0.6 ml (7.50 mmol) of ethyl iodide were sequentially added, and the mixture was stirred at room temperature for 5.5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The extract layer was washed with saturated brine, dried over magnesium sulfate, and concentrated. The concentrate was applied to a silica gel column and poured out with a mixed solvent of hexane and ethyl acetate at a ratio of 20: 1 to give 2-t-butyl-3-ethoxy-1-methoxy-1.
-(3-Methoxyphenyl) -1-propene (Compound [43]) was obtained as a colorless oily substance at 1.00 g and a yield of 93.7%.

¹ HNMR (300 MHz, CDCl ₃ ); δ
1.13 (t, J = 7.0Hz, 3H), 1.29 (s, 9
H), 3.25 (s, 3H), 3.29 (q, J = 7.0H
z, 2H), 3.69 (s, 2H), 3.82 (s, 3H),
6.84-6.90 (m, 1H), 6.94-6.99
(M, 2H), 7.22 to 7.29 (m, 1H) ppm IR (liquid film); 2956, 2868, 163
6,1598,1580 cm ^-1 Mass (m / z,%); 278 (M ⁺ , 31), 263
(8), 233 (22), 221 (100), 217 (4
2)

(Reference Example 26)

Embedded image

Compound [43] synthesized in Example 15 1.
00 g (3.60 mmol) and 305 mg (7.63 mmol) 60% sodium hydride were added to 10 ml anhydrous DMF,
The mixture was stirred at 0 ° C under an argon atmosphere. 0.53 ml (7.16 mmol) of ethanethiol was added to this solution, and the mixture was stirred for 10 minutes and then heated and stirred at 120 ° C. for 3 hours. The reaction mixture was poured into saturated saline and extracted with ethyl acetate. The extract layer was washed with saturated brine and water, dried over magnesium sulfate, and concentrated. The concentrate was applied to a silica gel column and poured out with a 7: 1 mixed solvent of hexane and ethyl acetate.
-T-butyl-3-ethoxy-1- (3-hydroxyphenyl) -1-methoxy-1-propene (compound [4
4]) was obtained as a colorless oil in a yield of 51.8% (492 mg).

¹ HNMR (300 MHz, CDCl ₃ ); δ
1.13 (t, J = 7.0Hz, 3H), 1.28 (s, 9
H), 3.24 (s, 3H), 3.29 (q, J = 7.0H
z, 2H), 3.69 (s, 2H), 4.78 to 4.83
(M, 1H), 6.81 (ddd, J = 8.0, 2.6 and
0.9Hz, 1H), 6.87 (s with fine coupling,
1H), 6.94 (d with fine coupling, J = 7.6H)
z, 1H), 7.22 (dd, J = 8.0 and 7.6Hz,
1H) ppm IR (liquid film); 3320, 2956, 287
2, 1634, 1596, 1582 cm ^-1 Mass (m / z,%); 264 (M ⁺ , 30), 249.
(6), 219 (13), 207 (100), 203 (6
4), 161 (51)

(Reference Example 27)

Embedded image

Compound [44] 12 synthesized in Reference Example 26
4 mg (0.470 mmol) was dissolved in 1.5 ml anhydrous DMF,
The mixture was stirred at room temperature under an argon atmosphere. To this solution, 69 mg (1.01 mmol) of imidazole and 137 mg (0.909 mmol) of t-butyldimethylchlorosilane were added and stirred for 8 hours and 40 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The extract layer was washed with saturated brine and water, dried over magnesium sulfate, and concentrated. The concentrate was applied to a silica gel column and was poured out with a 1: 1 mixed solvent of hexane and dichloromethane, and 2-t-butyl-1- [3-
(T-Butyldimethylsiloxy) phenyl] -3-ethoxy-1-methoxy-1-propene (Compound [45])
Was obtained as a colorless oil with a yield of 152 mg and a yield of 85.6%.

¹ HNMR (300 MHz, CDCl ₃ ); δ
0.20 (s, 6H), 0.99 (s, 9H), 1.12.
(T, J = 7.0 Hz, 3 H), 1.28 (s, 9 H), 3.
23 (s, 3H), 3.26 (q, J = 7.0Hz, 2
H), 3.70 (s, 2H), 6.80 (ddd, J = 8.
1,2.5 and 1.0Hz, 1H), 6.86 (s with fin
e coupling, 1H), 6.95 (d with fine couplin
g, J = 7.6 Hz, 1 H), 7.19 (dd, J = 8.1 a
nd 7.6Hz, 1H) ppm IR (liquid film); 2956, 2936, 286
4,1634,1598,1578,1260,108
6 cm ^-1 Mass (m / z,%); 378 (M ⁺ , 31), 333 (1
3), 322 (25), 321 (100), 319 (1
5), 317 (31)

(Reference Example 28)

[Chemical formula 61]

Compound [45] 10 synthesized in Reference Example 27
5 mg (0.278 mmol) and 4 mg of TPP were dissolved in 30 ml of dichloromethane and stirred at 0 ° C under an oxygen atmosphere. This solution was irradiated with a Na lamp (180 W) for 7 hours. The reaction mixture was concentrated, applied to a silica gel column and poured out with a mixed solvent of hexane and dichloromethane of 2: 1. 3-t-butyl-4- [3- (t-butyldimethylsiloxy) phenyl] -3-ethoxymethyl- 4-methoxy-1,2-dioxetane (compound [46]) is 8
It was obtained as a pale yellow oil in 8 mg, yield 77.3%.

¹ HNMR (300 MHz, CDCl ₃ ); δ
0.20 (s, 3H), 0.20 (s, 3H), 0.81
(T, J = 7.0Hz, 3H), 0.99 (s, 9H), 1.
28 (s, 9H), 2.48 to 2.62 (m, 1H), 2.
94 (dq, J = 9.2 and 7.0Hz, 1H), 3.04
(S, 3H), 3.52 (d, J = 10.1Hz, 1H),
3.71 (d, J = 10.1Hz, 1H), 6.80 to 7.3
0 (m, 4H) ppm IR (liquid film); 2960, 2936, 160
4,1586,1256,1106 cm ^-1 Mass (m / z,%); 378 (M ⁺ -32,8), 321.
(13), 266 (25), 208 (24), 209 (1
00), 177 (33), 149 (18)

(Reference Example 29)

Embedded image

Compound [44] 48 synthesized in Reference Example 26
3 mg (1.83 mmol) was added to 6 ml of anhydrous toluene, and the mixture was stirred at 0 ° C under an argon atmosphere. To this solution 0.31 ml (2.22 mmol) triethylamine followed by 2-chloro-
1,3,2-dioxaphosphorane-2-oxide 0.17
5 ml (1.89 mmol) was added and the mixture was stirred at 0 ° C. for 10 minutes and then at room temperature for 50 minutes. The reaction mixture was concentrated, diethyl ether was added, and the insoluble material was filtered off. When the filtrate was concentrated, a crude product of 3- (2-t-butyl-3-ethoxy-1-methoxy-1-methoxy-1-propen-1-yl) phenylethylene phosphate (Compound [47]) was obtained as a colorless oil. Was obtained.

¹ HNMR (300 MHz, CDCl ₃ ); δ
1.15 (t, J = 7.0Hz, 3H), 1.28 (s, 9
H), 3.24 (s, 3H), 3.30 (q, J = 7.0H
z, 2H), 3.66 (s, 2H), 4.26 to 4.60
(M, 4H), 7.12-7.38 (m, 4H) ppm

(Reference Example 30)

[Chemical formula 63]

680 mg of the crude product of the compound [47] synthesized in Reference Example 29 was added to 8 ml of anhydrous DMF, and the mixture was stirred at room temperature under an argon atmosphere. To this solution, 94 mg (1.82 mmol) of sodium cyanide (95%) was added and stirred overnight. The reaction mixture was concentrated, 5 ml of 28% aqueous ammonia and 2 ml of THF were added, and the mixture was stirred for 1 day. The reaction mixture was concentrated, the concentrate was dissolved in water and washed with hexane. When the aqueous layer was freeze-dried, ammonium sodium 3-
(2-t-butyl-3-ethoxy-1-methoxy-1-
A crude purified product of propen-1-yl) phenyl phosphate (Compound [48]) was obtained as 733 mg as a colorless amorphous solid.

¹ HNMR (300 MHz, CD ₃ OD);
δ1.13 (t, J = 7.0Hz, 3H), 1.31 (s,
9H), 3.28 (s, 3H), 3.29 (q, J = 7.0)
Hz, 2H), 3.79 (s, 2H), 7.03 (d with f
inecoupling, J = 7.1Hz, 1H), 7.20 (broad
s, 1H), 7.29 (dd, J = 8.3 and 7.1Hz,
1H), 7.35 (d, J = 8.3Hz, 1H) ppm IR (KBr); 2960, 2868, 1634, 16
00, 1580, 1296, 1110 cm ^-1 Mass (FAB-pos, m / z,%); 389 ([M + H-N
H ₄ + Na] ⁺ , 28), 343 (24), 329
(23), 125 (100), 115 (19)

(Reference Example 31)

[Chemical 64]

Compound [48] 10 synthesized in Reference Example 30
6 mg (0.277 mmol) and 4 mg of TPP were dissolved in 30 ml of dichloromethane and stirred at 0 ° C under an oxygen atmosphere.
This solution was irradiated with light from a Na lamp (180 W) for 8 hours. The reaction mixture was concentrated, methanol was added to the concentrate, the insoluble material was filtered, and the mixture was concentrated again. The concentrate was mixed with methanol (2 ml) and 0.1% aqueous sodium hydrogen carbonate solution (2 m
It was dissolved in the mixed solvent of l) and filtered through a 0.45 µ polytetrafluoroethylene filter. 0.3 ml in the filtrate
HPL using a polymer-based reverse phase C18 preparative column.
The fraction eluted with C and eluted with a gradient of 0.1% aqueous sodium hydrogen carbonate solution and acetonitrile was freeze-dried. Methanol was added to the obtained lyophilized product to concentrate the soluble portion, and 3-t-butyl-3-ethoxymethyl-4-methoxy-4- (3'-phosphoryloxy) phenyl-1,2-dioxetanediene was obtained. The sodium salt (compound [49]) was obtained as a colorless amorphous solid.

¹ HNMR (300 MHz, CD ₃ OD);
δ 0.87 (t, J = 7.0 Hz, 3 H), 1.30 (s,
9H), 2.54 to 2.68 (m, 1H), 2.97 (d
q, J = 9.0 and 7.0Hz, 1H), 3.05 (s, 3
H), 3.51 (d, J = 10.2Hz, 1H), 3.76
(D, J = 10.2 Hz, 1 H), 6.96 to 7.10
(M, 1H), 7.24 to 7.44 (m, 2H), 7.56
~ 7.68 (m, 1H) ppm Mass (FAB-pos, m / z,%); 443 ([M + N
a] ⁺ , 20), 421 ([M + H] ⁺ , 24), 299
(22), 277 (23), 207 (17), 115 (1
00)

(Example 16)

Embedded image

Compound [11] 316 synthesized in Example 5
mg (1.26 mmol) was dissolved in 4 ml of anhydrous DMF and stirred at room temperature under an argon atmosphere. To this solution, 180 mg (2.64 mmol) of imidazole and 286 mg (1.90 mmol) of t-butyldimethylchlorosilane were added and stirred for 1 hour. The reaction mixture was poured into saturated saline and extracted with ethyl acetate. The extract layer was washed with saturated brine and water, dried over magnesium sulfate, and concentrated. The concentrate was applied to a silica gel column and poured out with a 2: 1 mixed solvent of hexane and dichloromethane, and 2-t-butyl-3- (t-butyldimethylsiloxy) -1-methoxy-1- (3-methoxyphenyl) was obtained. -1-propene (compound [50]) is 438
Obtained as a colorless oil in mg, yield 95.2%.

¹ HNMR (300 MHz, CDCl ₃ ); δ
-0.12 (s, 6H), 0.86 (s, 9H), 1.28
(S, 9H), 3.23 (s, 3H), 3.81 (s, 3)
H), 3.89 (s, 2H), 6.82 to 6.91 (m, 1
H), 6.88 (s, 1H), 6.96 (d with fine cou
pling, J = 7.5 Hz, 1 H), 7.18 to 7.29 (m,
1H) ppm IR (liquid film); 2956, 2932, 286
0,1638,1596,1580,1254,104
6 cm ^-1 Mass (m / z,%); 364 (M ⁺ , 5), 308 (2
4), 307 (100), 251 (19), 233 (6
5), 201 (61), 177 (17)

(Reference Example 32)

[Chemical formula 66]

Compound [50] 48 synthesized in Example 16
4 mg (1.33 mmol) and 60% sodium hydride 1
06 mg (2.65 mmol) was added to 5 ml of anhydrous DMF, and the mixture was stirred at 0 ° C under an argon atmosphere. 0.19 ml (2.57 mmol) of ethanethiol was added to this solution, and the mixture was stirred for 15 minutes, and then heated and stirred at 110 ° C. for 3 hours. The reaction mixture was poured into saturated saline and extracted with ethyl acetate. The extract layer was washed with saturated brine and water, dried over magnesium sulfate, and concentrated.
The concentrate was applied to a silica gel column and was poured out with a mixed solvent of hexane and ethyl acetate of 10: 1.
Butyl-3- (t-butyldimethylsiloxy) -1-
(3-Hydroxyphenyl) -1-methoxy-1-propene (Compound [51]) was obtained as a colorless amorphous solid in a yield of 221 mg and a yield of 47.5%.

¹ HNMR (300 MHz, CDCl ₃ ); δ
-0.10 (s, 6H), 0.87 (s, 9H), 1.27
(S, 9H), 3.24 (s, 3H), 3.88 (s, 2
H), 4.57 to 4.67 (m, 1H), 6.79 (dd
d, J = 8.1, 2.6 and 0.9 Hz, 1H), 6.85
(S with fine coupling, 1H), 6.94 (d with fi
ne coupling, J = 7.6Hz, 1H), 7.20 (dd,
J = 8.1 and 7.6Hz, 1H) ppm IR (KBr); 3320, 2956, 2860, 16
42, 1598, 1254, 1048 cm ^-1 Mass (m / z,%); 350 (M ⁺ , 4), 294 (2
2), 293 (100), 261 (14), 237 (1
9), 219 (64), 203 (18), 187 (76),
163 (22), 161 (22), 161 (18), 11
9 (24)

(Reference Example 33)

Embedded image

Compound [51] 27 synthesized in Reference Example 32
8 mg (0.794 mmol) was dissolved in 3 ml of anhydrous DMF, and the mixture was stirred at room temperature under an argon atmosphere. To this solution, 115 mg (1.69 mmol) of imidazole and 228 mg (1.51 mmol) of t-butyldimethylchlorosilane were added and stirred overnight. The reaction mixture was poured into saturated saline and extracted with ethyl acetate. The extract layer was washed with saturated brine and water, dried over magnesium sulfate, and concentrated. The concentrate was applied to a silica gel column and was poured out with a mixed solvent of hexane and dichloromethane of 3: 1. 2-t-butyl-3- (t-butyldimethylsiloxy) -1- [3- (t-butyldimethylsiloxy) Phenyl] -1-methoxy-1-propene (compound [52]) was obtained as a colorless oily substance in a yield of 270 mg and a yield of 73.3%.

¹ HNMR (300 MHz, CDCl ₃ ); δ
-0.14 (s, 6H), 0.19 (s, 6H), 0.85
(S, 9H), 0.98 (s, 9H), 1.28 (s, 9
H), 3.22 (s, 3H), 3.90 (s, 2H), 6.7
6 to 6.83 (m, 2H), 6.96 (d with fine coup
ling, J = 7.6 Hz, 1 H), 7.17 (dd, J = 8.
8 and 7.6 Hz, 1 H) ppm IR (liquid film); 2960, 2936, 286
0, 1640, 1596, 1578, 1256, 104
6 cm ^-1 Mass (m / z,%); 464 (M ⁺ , 5), 408 (3
4), 407 (100), 351 (19), 334 (2
0), 333 (66), 302 (21), 301 (80)

(Reference Example 34)

[Chemical 68]

Compound [52] 80 synthesized in Reference Example 33
mg (0.172 mmol) and TPP (2 mg) were dissolved in dichloromethane (20 ml), and the mixture was stirred at room temperature under an oxygen atmosphere. This solution was irradiated with a Na lamp (180 W) for 3 hours. The reaction mixture was concentrated, applied to a silica gel column, and poured out with a mixed solvent of hexane and dichloromethane at a ratio of 4: 1. 3-t-butyl-3-[(t-butyldimethylsiloxy) methyl] -4- [3- (t -Butyldimethylsiloxy) phenyl] -4-methoxy-1,2-dioxetane (Compound [53]) was obtained as a colorless oily substance in 70 mg in a yield of 81.9%.

¹ HNMR (300 MHz, CDCl ₃ ); δ
-0.44 (s, 3H), -0.21 (s, 3H), 0.2
0 (s, 6H), 0.73 (s, 9H), 0.98 (s, 9
H), 1.31 (s, 9H), 3.00 (s, 3H), 3.6
4 (d, J = 10.8 Hz, 1 H), 4.08 (d, J = 1
0.8 Hz, 1 H), 6.78 to 7.28 (m, 4 H) ppm IR (liquid film); 2960, 2932, 286
0,1602,1586,1256,1086 cm ^-1 Mass (m / z,%); 464 (M ⁺ -32), 266 (2
8), 210 (22), 209 (100), 177 (1
9) 173 (73), 115 (23)

(Reference Example 35)

[Chemical 69]

Compound [36] 50 synthesized in Reference Example 20
4 mg (1.51 mmol) was added to 6 ml of anhydrous toluene, and the mixture was stirred at 0 ° C under an argon atmosphere. To this solution was added 0.25 ml triethylamine (1.79 mmol) followed by 2-chloro-
1,3,2-Dioxaphosphorane-2-oxide 0.1
36 ml (0.147 mmol) was added, and the mixture was stirred at 0 ° C for 10 minutes and then at room temperature for 3 hours. The reaction mixture was concentrated, diethyl ether was added, and the insoluble material was filtered off. When the filtrate was concentrated, 3- (2-t-butyl-1-isopropoxy-
A crude purified product of 3-neopentyloxy-1-propen-1-yl) phenylethylene phosphate (Compound [54]) was obtained as a colorless oil (664 mg).

¹ HNMR (300 MHz, CDCl ₃ ); δ
0.90 (s, 9H), 1.12 (d, J = 6.2Hz, 6
H), 1.28 (s, 9H), 2.77 (s, 2H), 3.5
1 (s, 2H), 3.74 (hept, J = 6.2Hz, 1
H), 4.20 to 4.57 (m, 4H), 7.11 to 7.35
(M, 4H) ppm

(Reference Example 36)

Embedded image

Compound [54] 66 synthesized in Reference Example 35
4 mg (1.51 mmol) was added to 7 ml of anhydrous DMF, and the mixture was stirred at room temperature under an argon atmosphere. To this solution, 80 mg (1.55 mmol) of sodium cyanide (95%) was added and stirred overnight. The reaction mixture was concentrated, the concentrate was dissolved in water and lyophilized to give sodium 3- (2-t-butyl-
730 mg of a crude product of 1-isopropoxy-3-neopentyloxy-1-propen-1-yl) phenyl-2′-cyanoethyl phosphate (compound [55]),
Obtained as a colorless amorphous solid.

¹ HNMR (300 MHz, CD ₃ OD);
δ 0.93 (s, 9H), 1.17 (d, J = 6.1Hz,
6H), 1.33 (s, 9H), 2.80 (t, J = 6.2
Hz, 2H), 2.81 (s, 2H), 3.64 (s, 2
H), 3.87 (hept, J = 6.1Hz, 1H), 4.15
(Dt, J = 7.8 and 6.2Hz, 2H), 7.04 ~
7.40 (m, 4H) ppm

(Reference Example 37)

Embedded image

710 mg of the crude product of the compound [55] synthesized in Reference Example 36 was added to 3 ml of THF, and the mixture was stirred at room temperature under an argon atmosphere. 28% ammonia water 5 in this solution
ml was added and stirred for 2 days. The reaction mixture was concentrated, the concentrate was dissolved in water and washed with hexane. When the aqueous layer was freeze-dried, sodium ammonium 3- (2-t-butyl-1-isopropoxy-3-neopentyloxy-
A crude purified product of 1-propen-1-yl) phenyl phosphate (compound [56]) was obtained as a colorless amorphous solid (562 mg).

¹ HNMR (300 MHz, CD ₃ OD);
δ 0.92 (s, 9 Hz), 1.15 (d, J = 6.2 Hz,
6H), 1.33 (s, 9H), 2.80 (s, 2H), 3.
65 (s, 2H), 3.89 (hept, J = 6.2Hz,
1H), 7.05 (d, J = 7.5Hz, 1H), 7.13
(S with fine coupling, 1H), 7.25 (dd, J =
8.2 and 7.5Hz, 1H), 7.37 (d with fine c
oupling, J = 8.2Hz, 1H) ppm IR (KBr); 2956, 2868, 1627, 15
99, 1578, 1294, 1110 cm ^-1 Mass (FAB-pos, m / z,%); 459 ([M + H-N
H ₄ + Na] ⁺ , 28), 431 (22), 329
(100), 307 (43), 125 (67), 1
15 (35)

(Reference Example 38)

Embedded image

Compound [56] 19 synthesized in Reference Example 37
8 mg (0.438 mmol) and 4 mg of TPP were dissolved in 30 ml of dichloromethane and stirred at 0 ° C under an oxygen atmosphere.
This solution was irradiated with light from a Na lamp (180 W) for 4 hours. The reaction mixture was concentrated, methanol was added to the concentrate, the insoluble material was filtered, and the mixture was concentrated again. The concentrate was added with methanol (1 ml) and 0.1% aqueous sodium hydrogen carbonate solution (1 m
It was dissolved in the mixed solvent of l) and filtered through a 0.45 µ polytetrafluoroethylene filter. HPLC on a preparative column of polymer-based reverse phase C18, 0.1
The fraction eluted with a gradient of aqueous sodium hydrogen carbonate solution and acetonitrile was freeze-dried. The obtained freeze-dried product was dissolved in water and subjected to HPLC using a polymer-based reverse phase C18 preparative column, and the fraction desalted with a gradient of water and acetonitrile was freeze-dried.
t-Butyl-4-isopropoxy-3-neopentyloxymethyl-4- (3'-phosphoryloxy) phenyl-1,2-dioxetane disodium salt (compound [5
7]) was obtained as an amorphous solid in a yield of 80 mg and a yield of 37.4%.

¹ HNMR (300 MHz, CD ₃ OD);
δ 0.79 (s, 9H), 1.00 to 1.13 (m, 3
H), 1.21 (d, J = 6.1Hz, 3H), 1.37
(S, 9H), 2.24 to 2.37 (m, 1H), 2.60
(D, J = 8.2 Hz, 1 H), 3.23 to 3.40 (m,
1H), 3.50 to 3.70 (m, 2H), 6.82 to 6.8
7 (m, 1H), 7.20 to 7.40 (m, 1H), 7.5
2 to 7.70 (m, 2H) ppm IR (KBr); 2976, 2872, 1588, 12
70,1104 cm ^-1 Mass (FAB-pos, m / z,%); 513 ([M + N
a] ⁺ , 17), 491 ([M + H] ⁺ , 37), 429
(50), 407 (29), 327 (52), 30
5 (100), 263 (38), 125 (65), 115
(49)

(Reference Example 17)

Embedded image

Compound [24] 824 synthesized in Example 8
mg (2.53 mmol) was dissolved in 10 ml of anhydrous DMF and stirred at room temperature under an argon atmosphere. To this solution, 202 mg (5.05 mmol) of 60% sodium hydride, 0.48 ml (5.11 mmol) of 2-methoxyethyl bromide and 73 mg (0.226 mmo) of tetrabutylammonium bromide.
l) was added and the mixture was heated with stirring at 100 ° C. for 5 hours. 220 mg (5.50 mmol) of 60% sodium hydride in this solution, 2
-Methoxyethyl bromide 0.50 ml (5.32 mmol)
And tetrabutylammonium bromide 81mg
(0.310 mmol) was further added, and the mixture was heated with stirring at 100 ° C. for 5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The extract layer was washed with saturated brine, dried over magnesium sulfate, and concentrated. The concentrate was applied to a silica gel column and poured out with a mixed solvent of hexane and ethyl acetate at a ratio of 10: 1 to give 1- (3-benzyloxyphenyl) -2-t-butyl-1-methoxy-3- (2-methoxyethoxy). ) −
630 mg of 1-propene (compound [58]), yield 6
Obtained in 4.9%.

Mp: 48.0-49.0 ° C. (colorless columnar crystals,
Recrystallized from methanol) ¹ HNMR (300 MHz, CDCl ₃ ); δ1.29
(S, 9H), 3.22 (s, 3H), 3.30 (s, 3
H), 3.34 to 3.40 (m, 2H), 3.42 to 3.48.
(M, 2H), 3.78 (s, 2H), 5.08 (s, 2
H), 6.92 to 7.00 (m, 2H), 7.00 to 7.04
(M, 1H), 7.22 to 7.48 (m, 6H) ppm IR (KBr); 2952, 2928, 2900, 16
28, 1596, 1582 cm ^-1 Mass (m / z,%); 384 (M ⁺ , 27), 327 (1
0), 309 (11), 293 (21), 251 (55),
161 (13), 91 (100)

(Reference Example 39)

[Chemical 74]

The compound [58] 34 synthesized in Example 17
1 mg (0.8888 mmol) and 10% Pd-C (30 mg) were added to 4.5 ml of a 2: 1 mixed solvent of ethyl acetate and methanol, and the mixture was stirred under a hydrogen atmosphere at room temperature for 5 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated. The concentrate was applied to a silica gel column and poured out with a mixed solvent of hexane and ethyl acetate at a ratio of 5: 1 to give 2-t-butyl-1-
(3-hydroxyphenyl) -1-methoxy-3- (2
-Methoxyethoxy) -1-propene (compound [5
9]) was obtained as a colorless oily substance in a yield of 90.4% (236 mg).

¹ HNMR (300 MHz, CDCl ₃ ); δ
1.27 (s, 9H), 3.34 (s, 3H), 3.41
3.47 (m, 2H), 3.48 (s, 3H), 3.59 ~
3.65 (m, 2H), 3.64 (broad s, 2H), 6.
77 (s with fine coupling, 1H), 6.83 (dd
d, J = 8.0, 2.6 and 0.9 Hz, 1H), 6.89
(D with fine coupling, J = 7.7Hz, 1H), 7.
22 (dd, J = 8.0 and 7.7 Hz, 1 H), 7.41
(Broad s, 1H) ppm IR (liquid film); 3384, 2952, 283
6, 1634, 1596, 1582 cm ^-1 Mass (m / z,%); 294 (M ⁺ , 32), 237 (2
4), 219 (20), 218 (24), 203 (87)
162 (26), 161 (100)

(Reference Example 40)

[Chemical 75]

Compound [59] 10 synthesized in Reference Example 39
5 mg (0.357 mmol) was dissolved in 2 ml of anhydrous DMF and stirred at room temperature under argon atmosphere. To this solution, 52 mg (0.764 mmol) of imidazole and 98 mg (0.65 mmol) of t-butyldimethylchlorosilane were added and stirred for 5 hours. The reaction mixture was poured into water and extracted with ethyl acetate.
The extract layer was washed with saturated brine and water, dried over magnesium sulfate, and concentrated. The concentrate was applied to a silica gel column and was poured out with a mixed solvent of hexane and ethyl acetate at a ratio of 20: 1. 2-t-butyl-1- [3- (t-butyldimethylsiloxy) phenyl] -1-methoxy-3- (2-
Methoxyethoxy) -1-propene (compound [60])
Was obtained as a colorless oil with a yield of 124 mg and a yield of 85.1%.

¹ HNMR (300 MHz, CDCl ₃ ); δ
0.19 (s, 6H), 0.99 (s, 9H), 1.28
(S, 9H), 3.22 (s, 3H), 3.33 (s, 3
H), 3.31 to 3.37 (m, 2H), 3.41 to 3.47.
(M, 2H), 3.80 (s, 2H), 6.77 to 6.84
(M, 1H), 6.81 (d, J = 1.4Hz, 1H), 6.
94 (d with fine coupling, J = 7.6Hz, 1H),
7.19 (dd, J = 8.7 and 7.6 Hz, 1 H) ppm IR (liquid film); 2956, 2936, 163
6, 1596, 1578, 1260 cm ^-1 Mass (m / z,%); 408 (M ⁺ , 33), 351 (1
2), 333 (22), 317 (47), 276 (29),
275 (100), 249 (29), 219 (35), 1
79 (27), 121 (40)

(Reference Example 41)

[Chemical 76]

Compound [60] 55 synthesized in Reference Example 40
mg (0.134 mmol) and 4 mg of TPP were dissolved in 20 ml of dichloromethane, and the mixture was stirred at room temperature under an oxygen atmosphere. This solution was irradiated with a Na lamp (180 W) for 6.5 hours. The reaction mixture is concentrated and applied to a silica gel column with dichloromethane followed by dichloromethane and ethyl acetate 50: 1.
When it was made to flow out with a mixed solvent of 3-t-butyl-4-
[3- (t-butyldimethylsiloxy) phenyl] -4
-Methoxy-3- (2-methoxyethoxy) methyl-
42 mg of 1,2-dioxetane (compound [61]) was obtained in a yield of 70.8% as a yellow oil.

¹ HNMR (300 MHz, CDCl ₃ ); δ
0.20 (s, 6H), 0.99 (s, 9H), 1.28
(S, 9H), 2.69 (dt, J = 10.5 and 4.7)
Hz, 1H), 3.02 (dt, J = 10.5 and 5.3H
z, 1H), 3.04 (s, 3H), 3.16 (dd, J =
5.3 and 4.7Hz, 2H), 3.23 (s, 3H), 3.
61 (d, J = 10.3 Hz, 1 H), 3.77 (d, J =
10.3 Hz, 1 H), 6.85 (d with fine coupling,
J = 8.0 Hz, 1H), 6.90 to 7.20 (m, 2H),
7.26 (dd, J = 8.0 and 7.6 Hz, 1 H) ppm IR (liquid film); 2960, 2936, 160
2,1586,1256,1108 cm ^-1 Mass (m / z,%); 408 (M ⁺ -32,3), 266.
(27), 210 (22), 209 (100), 177
(19), 89 (21)

(Reference Example 42)

Embedded image

Compound [59] 41 synthesized in Reference Example 39
5 mg (1.41 mmol) was added to 6 ml of anhydrous toluene, and the mixture was stirred at 0 ° C under an argon atmosphere. To this solution 0.24 ml (1.72 mmol) triethylamine followed by 2-chloro-
1,3,2-Dioxaphosphorane-2-oxide 0.1
3 ml (0.141 mmol) was added, and the mixture was stirred at 0 ° C. for 20 minutes and then at room temperature for 1 hour and 20 minutes. The reaction mixture was concentrated, diethyl ether was added, and the insoluble material was filtered off. When the filtrate was concentrated, 3- [2-t-butyl-1-methoxy-3- (2-methoxyethoxy) -1-propene-1-
Ill] phenylethylene phosphate (compound [6
The crude product of 2)) was obtained as a colorless oil.

¹ HNMR (300 MHz, CDCl ₃ ); δ
1.28 (s, 9H), 3.24 (s, 3H), 3.35
(S, 3H), 3.32 to 3.52 (m, 4H), 3.37
(S, 2H), 4.30 to 4.60 (m, 4H), 7.12
~ 7.39 (m, 4H) ppm

(Reference Example 43)

Embedded image

560 mg of the crude product of the compound [62] synthesized in Reference Example 42 was added to 8 ml of anhydrous DMF, and the mixture was stirred at room temperature under an argon atmosphere. To this solution, 73 mg (1.42 mmol) of sodium cyanide (95%) was added and stirred overnight. The reaction mixture was concentrated, 4 ml of 28% aqueous ammonia was added, and the mixture was stirred for 1 day. The reaction mixture was concentrated, the concentrate was added to water and washed with hexane. When the aqueous layer was freeze-dried, sodium ammonium 3- [2-t-butyl-1-methoxy-3- (2-methoxyethoxy) -1-propen-1-yl] phenyl phosphate (compound [63]) was obtained.
Crude product of 525 mg was obtained as a colorless amorphous solid.

¹ HNMR (300 MHz, CD ₃ OD);
δ1.32 (s, 9H), 3.29 (s, 3H), 3.36
(S, 3H), 3.35 to 3.42 (m, 2H), 3.45
~ 3.51 (m, 2H), 3.84 (s, 2H), 7.05
(D with fine coupling, J = 6.8Hz, 1H), 7.
22 (broad s, 1H), 7.26 to 7.37 (m, 2
H) ppm IR (KBr); 2956, 1636, 1600, 15
78,1292,1218 cm ^-1 Mass (FAB-pos, m / z,%); 419 ([M + H-N
H ₄ + Na] ⁺ , 84), 343 (37), 329
(26), 321 (48), 125 (100)

(Reference Example 44)

Embedded image

Compound [63] 15 synthesized in Reference Example 43
1 mg (0.366 mmol) and 4 mg of TPP were dissolved in 30 ml of dichloromethane and stirred at 0 ° C under an oxygen atmosphere.
This solution was irradiated with light from a Na lamp (180 W) for 7 hours. The reaction mixture was concentrated, methanol was added to the concentrate, the insoluble material was filtered, and the mixture was concentrated again. The concentrate was added to methanol (3 ml) and 0.1% aqueous sodium hydrogen carbonate solution (3 m
It was dissolved in the mixed solvent of l) and filtered through a 0.45 µ polytetrafluoroethylene filter. HPLC on a preparative column of polymer-based reverse phase C18, 0.1
The fraction eluted with a gradient of aqueous sodium hydrogen carbonate solution and acetonitrile was freeze-dried. The obtained lyophilized product was dissolved in water and subjected to HPLC using a polymer-based reverse phase C18 preparative column, and the fraction desalted with a gradient of water and acetonitrile was freeze-dried.
43 mg of t-butyl-4-methoxy-3-[(2-methoxyethoxy) methyl] -4- (3'-phosphoryloxy) phenyl-1,2-dioxetane disodium salt (compound [64]), yield Obtained as an amorphous solid at 26.0%.

¹ HNMR (300 MHz, CD ₃ OD);
δ1.31 (s, 9H), 2.70 to 2.79 (m, 1
H), 2.96 to 3.08 (m, 1H), 3.06 (s, 3
H), 3.20 to 3.30 (m, 2H), 3.28 (s, 3
H), 3.61 (d, J = 10.4Hz, 1H), 3.81
(D, J = 10.4 Hz, 1 H), 6.98 to 7.14
(M, 1H), 7.26 to 7.42 (m, 2H), 7.56
~ 7.68 (m, 1H) ppm IR (KBr); 1605, 1585, 1281, 11
12 cm ^-1 Mass (FAB-pos, m / z,%); 473 ([M + N
a] ⁺ , 18), 451 ([M + H] ⁺ , 10), 401
(60), 299 (100), 277 (56), 125
(56), 115 (28)

* Test Example 1 * 3-t-butyl-4-methoxy-obtained in Reference Example 10
3-neopentyloxymethyl-4- (3'-phosphoryloxy) phenyl-1,2-dioxetane disodium salt (compound [18]) was added to a quaternary ammonium salt to a concentration of 0.2 mg / ml. BDMQ 0.4 mg / ml, 1 m
0.1M diethanolamine-hydrochloric acid buffer (pH 1) containing M magnesium chloride and 0.05% sodium azide.
After dissolving in 0.0) and stirring, 300 μl of this solution was placed in an assay cartridge and incubated. After incubation for 90 minutes, an alkaline phosphatase solution for EIA (Boehringer Mannheim Co., Ltd.) (3 mg / 0.3 ml) was added to 0.15 M sodium chloride, 1 mM magnesium chloride, 0.1 mM zinc chloride and 0.1 ml.
The enzyme solution prepared by diluting 154 times with 50 mM Tris / Cl buffer (pH 7.2) containing 1% sodium azide was used.
After adding 0 μl and stirring, the amount of luminescence was measured at 37 ° C. with time. For comparison, the amount of luminescence of commercially available AMPPD was measured under the same conditions. The result is shown in FIG.

* Test Example 2 * 3-t-butyl-4-methoxy-3-neopentyloxymethyl-4- (3'-phosphoryloxy) phenyl-1,2-dioxetane disodium obtained in Reference Example 10 1 mg of salt (compound [18]) was added to methanol d ₄
It was dissolved in (0.35 ml) and heated in a constant temperature bath at 60 ° C. Two
¹ H NMR was measured every ~ 3 hours. As a result, 3-
t-butyl-4-methoxy-3-neopentyloxymethyl-4- (3'-phosphoryloxy) phenyl-1,
2-dioxetane disodium salt (compound [18])
The half-life at 60 ° C was estimated to be 18.6 hours.

Commercially available AMPPD (3- (2'-spiroadamantane) -4-methoxy-4- (3 "-phosphoryloxy) phenyl-1,2-dioxetane disodium salt) was similarly measured. The half-life at was estimated to be 5.5 hours.

[0215]

The present invention is a simple method for producing an enol ether derivative. The enol ether derivative obtained by the present invention can be converted into a chemiluminescent 1,2-dioxetane derivative by reacting with singlet oxygen. The 1,2-dioxetane derivative is excellent in thermal stability, has a short time until the maximum light emission amount per unit time after the start of light emission, and has a high maximum light emission amount. It is possible to measure at, and it is easy to apply to high sensitivity analysis system. Furthermore, the molecule is designed to easily bind to amino acids or peptides,
It can be easily applied to labeled bodies and the like.

[Brief description of drawings]

FIG. 1 shows 3-t-butyl-4-methoxy-3-neopentyloxymethyl-4- (3′-phosphoryloxy) phenyl-1,2-dioxetane disodium salt (compound [18]) and alkaline phosphite. It is a figure which shows the relationship between the light emission intensity and time at the time of making it light-emit using tase. The results of AMPPD are also shown for comparison.

Embedded image

Continuation of front page (51) Int.Cl. ⁶ Identification number Office reference number FI technical display location // C07B 61/00 300 C07D 321/00

Claims (9)

[Claims] 1. A compound represented by the general formula: And a compound represented by the general formula: A compound represented by the general formula: embedded image which comprises reacting with an alkylating reagent or a silylating reagent represented by A method for producing a compound represented by the formula (in the formula, R ¹ , R ² and R ³
Is a hydrogen atom, an alkyl group or an aryl group, R ¹ ,
Any two members of R ² and R ³ can be joined together to form a cycloalkyl group. R ⁵ is an alkyl group or a cycloalkyl group. R ⁶ and R ⁷ are a hydrogen atom, an alkyl group or an aryl group, and R ⁸ is an alkyl group or —Si
It is a group represented by (R ¹⁰ , R ¹¹ , R ¹² ). Ar is an aryl group which is unsubstituted or substituted by R ⁹ , and R ⁹ is an alkoxyl group or a group represented by —OSi (R ¹⁰ , R ¹¹ and R ¹² ). R ¹⁰ , R ¹¹ and R ¹² are alkyl groups.
X is a halogen atom when R ⁸ is an alkyl group, an alkyl or arylsulfonyloxy group or an alkylsulfate group, and halogen when R ⁸ is a group represented by —Si (R ¹⁰ , R ¹¹ , R ¹² ). Is an atom. ). 2. A compound represented by the general formula: embedded image is reacted with an alkyl or aryl sulfonyl chloride or a halogenating reagent,
Then, the general formula: A reaction of an alcohol represented by the general formula: A method for producing a compound represented by the formula (in the formula, R ¹ , R ² and R ³
Is a hydrogen atom, an alkyl group or an aryl group, R ¹ ,
Any two members of R ² and R ³ can be joined together to form a cycloalkyl group. R ⁵ is an alkyl group or a cycloalkyl group. R ⁶ and R ⁷ are a hydrogen atom, an alkyl group or an aryl group, and R ¹³ is an alkyl group or an aryl group. Ar is an aryl group substituted with an unsubstituted or R ^9, R ⁹ is an alkoxy group or a -OSi
It is a group represented by (R ¹⁰ , R ¹¹ , R ¹² ). R ¹⁰ , R ¹¹
And R ¹² is an alkyl group. ). 3. A general formula: A method for producing a compound represented by the general formula: ## STR1 ## by reacting a compound represented by: with a hydride or an alkyl or aryl metal reagent (wherein R ¹ ,
R ² , R ³ , R ⁵ , R ⁶ , R ⁷ and Ar are the same as described above.
R ⁴ is a lower alkyl group. ). 4. A compound represented by the general formula: embedded image in the presence of a base. And a compound represented by the general formula: By reacting with an alkylating reagent represented by
Method for producing a compound represented by the general formula: embedded image (wherein R ¹ ,
R ² , R ³ , R ⁴ , R ⁵ and Ar are the same as above. X is a halogen atom, an alkyl or aryl sulfonyloxy group or an alkylsulfate group. ). 5. A compound represented by the general formula: embedded image and the general formula: embedded image in the presence of an acid catalyst. A process for producing a compound represented by the general formula: embedded image (wherein R ¹ ,
R ² , R ³ , R ⁴ , R ⁵ and Ar are the same as above. ). 6. A compound represented by the general formula [Chemical formula 1] obtained by reacting a compound represented by the general formula [Chemical formula 6] with a hydride or an alkyl or aryl metal reagent is used as a raw material. The method according to claim 1, wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ ,
R ⁶ , R ⁷ and Ar are the same as above. ). 7. A compound represented by the general formula [Chemical formula 1] obtained by reacting a compound represented by the general formula [Chemical formula 6] with a hydride or an alkyl or aryl metal reagent is used as a raw material. The method according to claim 2, wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ ,
R ⁶ , R ⁷ and Ar are the same as above. ). 8. A compound represented by the general formula: embedded image obtained by reacting a compound represented by the general formula: with an alkylating reagent represented by the general formula: The method according to claim 1, wherein a compound represented by the general formula: ## STR1 ## obtained by reacting a compound represented by: with a hydride or an alkyl or aryl metal reagent is used as a raw material. R ¹ , R ² , R ³ , R ⁴ , R ⁵ ,
R ⁶ , R ⁷ , Ar and X are the same as defined above. ). 9. A compound represented by the general formula: embedded image obtained by reacting a compound represented by the general formula: embedded image with a compound represented by the general formula: embedded image in the presence of an acid catalyst. The method according to claim 2, wherein a compound represented by the general formula: ## STR1 ## obtained by reacting a compound represented by the formula with a hydride or an alkyl or aryl metal reagent is used as a raw material. ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶
And Ar are the same as above. ).