JPS61271234A - Vinyl fluoride derivative and production thereof - Google Patents

Abstract

NEW MATERIAL:A vinyl fluoride derivative shown by the formula I [A is group shown by the formula II (R<1> is alkylene), formula III, etc.; B is group shown by the formula IV (R<2> is monohydric alcohol residue or H; m is 0-5) or group shown by the formula V(X is OH, halogen or nitrile; n is 1-5)]. EXAMPLE:Ethyl 5,6-dihydroxy-2-fluoro-2-hexenoate 5,6-acetonide(3). USE:An intermediate for a fluorine-containing physiologically active substance. PREPARATION:An aldehyde shown by the formula VI is reacted with Wittig reaction shown by the formula VII (R<4> is alkyl, aryl, or aralkyl), and, if necessary, further reduced, and halogenated and/or subjected to carbon increasing reaction to give a vinyl fluoride derivative shown by the formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel vinyl fluoride derivative and a method for producing the same.

In the field of developing physiologically active substances, long-chain alkyl compounds having a carboxyl group or a derivative group thereof (such as an ester group) at the end are useful as intermediates for physiologically active substances having a carboxyl group. For example, prostaglandins, prostacyclin, thromboxane, leukotrief. It is useful as an intermediate for arachidonic acid and other physiologically active substances whose structure includes a long-chain hydrocarbon group having a carboxyl group at the end. On the other hand, compounds in which fluorine atoms are introduced into physiologically active substances or similar compounds thereof are the subject of various studies because new physiological activities due to the fluorine atoms are expected. In synthesizing such fluorine atom-containing physiologically active substances, the above-mentioned intermediates containing fluorine atoms are often required. Many relatively simple vinyl fluorides are known as these fluorine atom-containing intermediates (for example, Journal of the Society of Organic Synthetic Chemistry, Vol. 42, pp. 770-808, 1984).
Year).

However, vinyl fluorides with relatively long hydrocarbon chains are not well known.

The present invention provides a novel vinyl fluoride derivative useful as an intermediate for the above-mentioned fluorine-containing physiologically active substances and a method for producing the same, and consists of the following two inventions.

A vinyl fluoride derivative represented by the following formula (I).

(However, R1 is an alkylene group having 1 to 5 carbon atoms that forms a 5 to 6-membered ring as a whole) B: +CIh) ac
OOR', alloy is 4GH2'+nX but R
2 is a monohydric alcohol residue or a hydrogen atom.

X is a hydroxyl group, a halogen atom, or a nitrile group m is an integer of O to 5 n is an integer of 1 to 5 Aldehydes represented by the following formula (II) and the following formula (II
Production of a vinyl fluoride derivative represented by the above formula (I), which is characterized by reacting the Witsch reagent represented by I) and further performing reduction, halogenation, and/or carbonization reactions as necessary. Law.

(II) (III) However, R4: alkyl group, aryl group.

Alternatively, aralkyl group B: As the above-mentioned vinyl fluoride derivative of the present invention, a compound in which A is an aldehyde group is ultimately useful. However, in the step of synthesizing compounds in which A is an aldehyde group, which are useful as intermediates for various physiologically active substances, if A is an aldehyde group, the aldehyde group may be involved in the reaction; is preferably a group as described above that can be converted into an aldehyde group, that is, a compound in which A is an oxygen atom-containing 5- to 6-membered ring or a dihydroxyethyl group can be used as a synthetic intermediate for a compound in which A is an aldehyde group. Useful. Compounds in which A is an aldehyde group can be reacted, for example, with Witsch reagents other than those mentioned above, especially Rei-Nochig reagents having long-chain hydrocarbon groups or cyclic hydrocarbon groups, to produce desired fluorine-containing physiologically active substances or new substances. Used in the synthesis of synthetic intermediates. In addition, R1 is a branched or linear fullkylene group or alkylidene group that forms a 5- to 6-membered ring containing an oxygen atom (i.e., a 1.3-dioxolane ring or a 1.4-diogythane ring), and especially Suitable groups include methylene group, ethylene group, propylene group, ethylidene group, and impropylidene group, with impropylidene group and methylene group being particularly preferred.

B is a linear alkyl group having a specific functional group at its terminal or a carpoxy group having no linear alkyl group. The vinyl fluoride derivative of the present invention, which is particularly useful as an intermediate for fluorine-containing physiologically active substances, has B of 4GH2) 500
0R? It is a group represented by Although R2 may be a hydrogen atom, it is usually a residue of a monohydric alcohol that forms an ester, and a hydrocarbon group having 1 to 10 carbon atoms is particularly suitable. In particular, an alkyl group is preferred, but it may also be an alkenyl group or an aralkyl group, and 6m, which is most preferably an alkyl group having 1 to 6 carbon atoms, may be O as described above, especially 2 or 3 A compound in which B is preferably a group represented by 4CH2f nX is useful as a synthetic intermediate for a compound in which B is a group represented by 4CH2) ncOOR'. However, it is not limited to this, and in particular, compounds where X is a hydroxyl group,
It can also be used as an intermediate for the purposes of the present invention.

In particular, n is preferably an integer of 1 to 3, and the halogen is a chlorine atom.

A bromine atom or an iodine atom is preferred, and a bromine atom and an iodine atom are particularly suitable.

The vinyl fluoride derivative of the present invention can be obtained by reacting the aldehyde represented by the formula (n) with the Witsch reagent represented by the formula (III). General methods for producing Witsch reagents and reaction methods using them are well known.

For example, rchem, Lett, 1978.1001
J and rJ, Med.

Chew, 23, 1077 (IHO) J. By this known production method, the formula (II)
The Witsch reagent represented by I) can be obtained, and the above-mentioned aldehydes and this Witsch reagent can be reacted according to known reaction methods. The above formula (III)
B is 4 CH2) as the Witsch reagent represented by
a Compounds that are COOR2, particularly GOOR2 whose m is 0, are preferred; R4 has 1 to 10 carbon atoms;
An alkyl group, or a phenyl group or benzyl group which may have a substituent is preferable, and in particular an alkyl group having 1 to 4 carbon atoms.
The alkyl group is preferred.

The compound obtained by reacting the aldehyde represented by the above formula (■) with the Witch reagent represented by the formula (III) contains a part of the vinyl fluoride derivative compound group represented by the above formula (I). can get. Further, if necessary, other vinyl fluoride derivatives can be obtained by subjecting the obtained compound 1 to reduction, halogenation, and carburization reaction (reaction to extend carbon steel). In particular, (([2 arrow COOR2 becomes B
A carburization reaction is carried out to increase the m of the group, and a carburization reaction is employed to increase m to 2 or 3 from a compound where 1m is O. Because of this carburization reaction, B is often (
Compounds that are CTo ) nX are used. i.e. 4CH2) via a compound where B is (CH2) nX
A compound in which the number of m in B, which is acOOR', is increased is obtained.

Flowcharts of reactions and compounds in the Examples described below are as follows (see Examples for abbreviations).

(l)
Compound (I) is an example of a compound represented by the above formula (IT), and compound (I) is an example of a compound represented by the above formula (IT).
2) is an example of the compound represented by the above formula (III). Compound (3).

(4), (5), (7), (8), (I0), (I1)
, (I2) and (I3) are examples of the vinyl fluoride derivative of the present invention represented by the above formula (I). As mentioned above, a preferred compound in the present invention is a compound in which A is an aldehyde group and B is (CH2)□GOOR2, which is compound (I3) in the above example. This compound is synthesized from a compound before A is converted into an aldehyde group, such as compound (I1). Compounds (3) and (7), which have exactly the same structure (excluding R2) except that the number of n is smaller than compound (I1), can be synthesized from compound (!1) to compound (
Compound (I3) has exactly the same structure as compound (I3) except that the number of n is small, using almost the same synthesis method as that of
A compound having an aldehyde group (excluding R2) is obtained. Compounds having aldehyde groups with a small number of n are also useful intermediates like compound (I3).

An example of synthesizing 5-fluoroarachidonic acid ester from (I3) will be shown as a reference example to be described later. Arachidonic acid itself has physiological activity and is an extremely important compound as a starting material for prostagrangees, leukotrienes, thromboxanes, etc. in living organisms. Therefore, 5-fluoroarachidonic acid is a compound considered to be useful as a biosynthesis inhibitor or antagonist of prostagranges and the like.

EXAMPLES The present invention will be specifically explained below with reference to Examples, but the present invention is not limited to these Examples.

Example Diynpropylamine (3.3 mQ, 30 mmol
) was added n-BuLi (I, 4% hexane solution 24°5 gmol) and stirred for 20 minutes, followed by ethyl diethylphosphonofluoroacetate (2) (8.5g,
35 mmol) and incubated at -78°C for 5 minutes and at 0°C for 20 minutes.
Stir for a minute. After cooling the reaction solution to -78°C, 3,4-dihydroxybutanal 3,4-acetonide (I) (5,
An ether solution (5 sl) of 1 g, 35+u+ol) was added thereto, and after stirring at -78°C for 2 hours, brine was added and extracted with ether. Wash the ether extract with water and dry it! (MgS
After Oa), it was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography, and 88 g (yield 85%) of (3) was obtained from the fraction eluted with n-hexane ethyl acetate (5:1). Ta.

(3): bp 115-120℃/3a+mHg; I
H-NMR (CD, Cl5) 6.00 (IH, dt, J
= 21and7.5)1z)”.

19F-NMR (CDC: 13) 55, lppm (d, J=21Hz)
7.0849 tetramethylsilane was used as an internal standard.

"" M using Red Fist benzotrifluoride as internal standard
S: Mass spectrum, calculated values in [ ] under argon flow (3
) (8.88 g, 29.85 mmol) at 8° C. in an ether solution (30 mmol) (0.7 M hexane solution 4).
Add 21) and stir for 30 minutes. Brine was added to the reaction solution, filtered through Celite, the filtrate was extracted twice with ether, dried over Hg5Oa, and then extracted under reduced pressure. M shrinks. The residue was purified by silica gel column chromatography (hex
ane:Ac0Et*l:1) L/, (4) to 5
．． 1 g (80% yield) is obtained.

(4): IH-NMR (CDCh) 5.19 (I)
l, dt, J-21and7.5 Hz, -CH=CF
-) IR: 3400 cm-1 MS CsH+zF, +03[175,07f391
175.0761 Under a stream of argon, THF was added to LiBr (f (g, 57.2a + mol), which had been thoroughly dried in advance).
Add the solution (30 ml) and cool to -78°C, (4)
(3℃g, 18.9mmol) was added, and after stirring for 5 minutes,
n-BuLi (I, 4M, 13.3sl, 19+mo
Add l) and stir for 30 minutes. The methanesulfonyl chloride mixture was further stirred at -78°C for 30 minutes, the reaction temperature was gradually raised to room temperature, and the mixture was stirred for 2 hours. Add brine to the reaction solution, extract twice with ether, and wash the organic layer twice with water. Organic layer M
After drying with gSOn and concentrating under reduced pressure, (5) It 4.5
5 g (yield 95.15K) is obtained.

(5): II-NMR (CDCI: +) 5.30 (
IH. , dt, J- 18 and 7, 5 Hz, -CH
TomiOF-) ~ NS C9B+4F+028r+ [252.018
01 252.0157 Diisopropylamine y (d=0.894, 0.43s+
n-
Add BuLi (3.3 ml of I.4M hexane solution) and stir for 20 minutes, then add phenylthioacetic acid ethyl ester (830 g, 4.7+s layer 01) and stir for 15 minutes, then add hexamethylphosphoric triamide. (HM
PA) (Mso.179.20, d-1.03, 3m
After adding (5) (Ig.3.1) and stirring for 5 minutes,
95 mmol) was added, and the temperature was gradually raised to room temperature.
Stir for 0 minutes. Add brine to the reaction solution and dilute with ether.
After extraction, the organic layer was washed twice with water and dried with MgSO4.
Concentrate under reduced pressure and purify the residual liquid by silica gel column chromatography (hexane: AcOEts 5:1)
l,, (6) as 1, 19. (yield: 82z).

Thioester of the above (Ei) (I. 19g, 3.23
Raney in a solution (30 ml) of 1 ol)
Add Xi(W2) little by little and stir for 15 minutes. After the reaction was completed, the reaction solution was filtered through Celite and extracted twice with ether.

Mg. After drying with sOs, concentrate under reduced pressure. The residue was purified by silica gel column chromatography (hexa
ne:AcOEt=5:1) I,, (7) 577m
g (yield 88.7%) is obtained.

(7): IH-NMR (CDC13) 5.12 (I
H, dt, J- 21and7, 5Hz, -CH Hatake C
F-) IR: 174O c layer-1 MS (+2H+:+F+04[245.1188]
245.118B.

(7) In an ether solution (50 ml) of (2.4 g, 9.23 layers 1 o 1), old BA was added at -78°C under an argon stream.
Add a hexane solution of L-H (0.7M, 10.4ml) and stir for 1 hour. Brine was added to the reaction solution, filtered through Celite, extracted twice with ether, and the a-layer was extracted twice.
Wash twice with water, dry with MgSO4, and concentrate under reduced pressure.

The residual liquid was purified by silica gel column chromatography (h
Exane:AcOEt-2:1) L , (8) was obtained in an amount of 1.87 Kg (yield: 93.3%).

(8): IH-NMR ((DC13) 5.12(I
8, dt, J-21 and 7, 5Hz, -CH=CF
-) NS C++H+9F+03 [218.131712
18.129B tonido (8) (8) (1.7 g, 7.8 m intestine) and triethylamine (2.713 g, 20.0 m in methylene chloride solution at -23°C under an argon atmosphere) Methanesulfonyl chloride (MW 114.
5, d-1, 48, 0.111ml, 11.8s+
add nol). Stir for 10 minutes. Add brine to the reaction solution and extract with ether. The ether extract was washed twice with water, dried (MgSOa), and concentrated under reduced pressure to obtain (9)
2.0 g (yield 80%) is obtained.

(9): IH-NNR (CDC13) 4.99 (I
H, dt, J=7.5and21Hz, -CH=CF-
) Is Cth H + sFOsS (M・-〇〇3) [2B1
．． 0857] 281.0842 Under argon flow. K.C.
IINF solution of N (I2.3g, 4111 layers 01) (
After adding a catalytic amount of 18-crovn-8 to (50 ml), (9) (I.8 g, 8.0 mmol) was added,
Stir at 50°C for 5 hours. Add brine to the reaction solution, extract twice with ether, and wash the organic layer twice with water. After drying with MgSO4, it is concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 4-hexane (AcOEt=5).
:1) to obtain 1.2g of (io) (yield 88%)
).

(I0): l)l-NMR (GDIII:13)
5.21 (IH, dt, J=21and7.5Hz,
-CH=CF-) 820 (2+112) of NaOH (28 mmol)
(I0) (800 mg,
2.64 mmol) was added, heated under reflux for 24 hours, and then returned to room temperature. 9. The reaction solution was diluted with ether (I0 ml), and 10% HGI was added at 0°C to make it acidic. 8. The reaction solution was diluted with ether twice. Extract and wash the organic layer twice with water, NgSOs
After drying, concentrate under reduced pressure. The residue was diluted with methylene chloride (5 layers), and an ether solution of CH2N2 was added at 0°C until N2 stopped bubbling. After stirring for an additional 5 minutes, the reaction solution was evaporated, and the residue was subjected to silica gel column chromatography (
- Purified by (hexane: AcOEtg2:
1) 550 mg (yield 80%) of L, (I1) was obtained.

(I1): 'H-NMR (GDCI3) 5.05
(IH, dt, J=2!and7.5Hz, -CH=
CF-) IR: 1740 cm-1 MS Cl2H18F104 [245,1188
1245,1185 (I1) (3EfOmg, 1.38
concentrated hydrochloric acid (0 mmol) in MeOH solution (7.5 ml)
, 5ml) was stirred at room temperature for 1 hour, and then ether (
After diluting with I0ml) and neutralizing by adding NaHCO3,
Filter using Celite, dry the filtrate with NgSO, and concentrate under reduced pressure to obtain 207 g (yield: 882) of (I2).

(!2): IH-MNR (CDCh) δ:5.
07 (IH, dt, J=21and7.5Hz) (I2
) (I 52 mg, 0.
．． Add 37480mg, 1.03s proverb), 10
Stir for 1 minute, dilute with ether (I0 ml), filter through Celite, add water to the filtrate, extract twice with ether, wash with NaHCO3 water, dry over MgSO4, and concentrate under reduced pressure. (I3) 78 mg (yield 58z) was obtained.

(I3): IH-MNR(CDCh) δ:5.
30 (IH, dt, J=21 and 7.5Hz).

9.78 (IH, -CHO) Reference Example 5 - Synthesis of methyl fluoroarachidonate [(3z, 8z
)-dodecadien-1-yl] n-butyllithium (I°4M
Hexane solution, 0.3m+! , 0.42txm□1)
was added dropwise at -78°C, and after stirring for 15 minutes, hexamethylphosphoric acid triamide (HMPA) (0.81ml) was added.
Stir for a minute. To this reaction solution (I3) (78 mg, 0.
After stirring for 30 minutes, the reaction mixture was heated to room temperature and poured into a saturated aqueous sodium bicarbonate solution, extracted twice with ether, washed with water (2
After drying (anhydrous magnesium sulfate), concentrate under reduced pressure. The residue was purified using a silica gel column chromatograph (hexane:ethyl acetate (20:1)).

33 mg (yield 24%) of the target product was obtained: IH-NMR
(CDCh), δ2.30 (2H, dt, J-7
,2,23Hz).

5.05 (II (, dt, J-21, 4, 8Hz)
; I9F-NMR (CDCh).

40.59 (dt, J-22,8Hz); MS (m
/e), 338 (N◆).

Claims (1)

[Claims] 1. Vinyl fluoride derivative represented by the following formula (I) ▲There are numerical formulas, chemical formulas, tables, etc.▼……………………(I
) However, A: ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, or ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (However, R^1 is an alkylene group) B;- (CH_2)-_mCOOR^2 or -(
CH_2)-_nX However, R^2 is a monohydric alcohol residue or a hydrogen atom. X is a hydroxyl group, a halogen atom, or a nitrile group m is an integer from 0 to 5 n is an integer 2 from 1 to 5;
Production of a vinyl fluoride derivative represented by the following formula (I), which is characterized by reacting the Witschig reagent represented by II) and further performing reduction, halogenation, and/or carbonization reactions as necessary. Law. ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(III) However, R^4: Alkyl group, aryl group, or aralkyl group B: -(CH_2)-_mCOOR ^2, or -(
CH_2)-_nXR^2 is a residue of a monohydric alcohol or a hydrogen atom,