JPS61155361A - Fluorine-containing sulfonyl compound - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (Rf is fluorine-containing aliphatic group; R<1> is aliphatic or aromatic group; R<2> is H, aliphatic group, aromatic group, OH, alkoxy, etc.; R<3> and R<4> are H, aliphatic group, aromatic group, cyano, carboxyl, etc.; R<5> and R<6> are H or aliphatic group). EXAMPLE:1-Phenylsulfonyl-2-trifluoromethyl-4-phenylbutan-4-one. USE:A synthetic intermediate for physiologically active substance. For example, it is useful as a synthetic intermediate for amino acid, hydroxyacid, etc., to give the compounds in high yield. PREPARATION:The compound of formula I can be prepared by adding benzenethiol to 3,3,3-trifluoropropene of formula II in NaOH+EtOH at 90 deg.C, reacting the components with each other for 4 days, reacting the resultant sulfide of formula III with sulfuryl chloride in CCl4 under refluxing, oxidizing the reaction product to sulfone with m-chloroperbenzoic acid in CH2Cl2, and dehydrochlorinating the reaction product with 1,8-diazabicyclo[5,4,0]-undecene in CH2Cl2 at room temperature.

Description

DETAILED DESCRIPTION OF THE INVENTION A. Field of Industrial Application The present invention relates to fluorine-containing sulfonyl compounds.

BACKGROUND OF THE INVENTION Physiologically active substances having a trifluoromethyl group, for example, have been attracting attention in recent years. In particular, trifluoromethyl group is one of the important groups constituting pharmacologically effective substances.
(Y, Kobay
ashi and 1. Kumadaki.

Acc, Cheo+, Res, , lj, , 197
(1978) ).

The following three methods are used to synthesize trifluoromethylated compounds.
There are two types.

(II Method of converting carboxylic acid or trichloromethyl groups by the action of gaseous sulfur tetrafluoride or hydrogen fluoride (G, A, Boswell L Jr, + w.

C, Ripka+ R, M, 5cribner+C,
W, Tullocl:” Organic Rea
ctions'', 21, 1 (1974))
.

(2) Substitution or addition reactions using reactive trifluoromethyl intermediates containing trifluoromethyl radicals or ions (Y, Kobayashi, K, Yas+amo
to.

and l, Ku+wadaki, J, C
hew, Soc,, PerkinI, Ni, 2775
).

(313l Method of using trifluoromethylated molecules as building units [Y, Koba-y
ashi, T., Kagai, 1. Kumadaki
, M., Takahaahian and T., Yamauc.
hi, Chel, Phars+, Bul1443
82 (1984)).

OBJECT OF THE INVENTION An object of the present invention is to provide a fluorine-containing sulfonyl compound useful as an intermediate for the synthesis of physiologically active substances.

26 Structure of the invention and its effects, that is, the present invention has the general formula: , hydroxyl group,
Alkoxyl group, amino group or alkylamino group; R2 and R4 are hydrogen atoms, aliphatic or aromatic groups, cyano groups, carboxyl groups, -GOOR' groups or -CON
R'R" group (R' is an aliphatic group, R1 and R9 are a hydrogen atom or an aliphatic group); R' and R6 are a hydrogen atom or an aliphatic group.] It is related to compounds.

This fluorine-containing sulfonyl compound (hereinafter referred to as the compound of the present invention) has a fluorine-containing aliphatic group (R2) in the molecule, so it is useful as a synthetic intermediate for amino acids, oxyacids, etc. It is something. Moreover, since it can be synthesized from a starting material having a sulfonyl group, it can be synthesized in high yield, as will be clear from what will be described later.

In the above general formula of the compound of the present invention, Rt is -CF3
() fluoromethyl group) is preferable, but
In addition, -Ct F s, -(n)CsFt, -(i)C
3rd floor? , -(n) C4F? , -(tert)Ca
F? Perfluoroalkyl groups such as these may be used, and the number of carbon atoms is preferably IO or less in consideration of raw material availability and solvent solubility.

Further, R1 and R1 may be the same or different groups,
In the case of an aliphatic group, an alkyl group such as a methyl group, ethyl group, or propyl group, or an alkenyl group having the same number of carbon atoms;
Alkynyl groups may be applied, but the number of carbon atoms is 1 to
A value of 10 is desirable.

R2 may also be an alkoxyl group (-OR) having an alkyl group having the same number of carbon atoms as above, or an alkylamino group (-NHR1-NR1) eR' and R
2 may be an aromatic group such as a phenyl group, but especially R1
is preferably a phenyl group, where R1 and R8
may each have a suitable substituent, but may not have one.

In addition to hydrogen atoms, R3 and R4 also contain the same or different alkyl groups, carboxyl groups, and ester groups (-
COOR), may be an amide group (-CONHR),
Rs and R- usually may be hydrogen atoms, but may also be the same alkyl groups as mentioned above.

Next, the compound of the present invention will be explained in detail along the synthesis process, but here, 1-phenylsulfonyl-3
, 3,3-) Lifluoropropene is used as a building unit. This 1-phenylsulfonyl-3,3,3-trifluoropropene is an acceptor for the Michael addition reaction.
r) shows high reactivity.

l-Phenylsulfonyl-3,3,3-)lifluoropropene 1 can be synthesized from 3.3°3-trifluoropropene 2 as shown in the following formula.

That is, benzenethiol was added to 2 at 90°C in NaOH + EtOH, and the reaction was carried out for 4 days to convert sulfide 3 to 51
% yield. The sulfide was then reacted with sulfuryl chloride in CC1a under reflux for 12 hours and further oxidized to the sulfone with mCPBA (metachloroperbenzoic acid) in CHtClt, followed by CHz Cl
in DBU (1°8-diazabicyclo(5,
4,0) undecene) to remove HCII by 46%
obtained in a yield of .

Other synthesis methods include those shown by the following formula.

That is, a mixture of stereoisomers of 1-chloro-3,3,3-)lifluoropropene 4 is reacted with one equivalent of benzenethiol. At this time, the reaction is carried out in NaOH+EtOH at 50°C for 1 day, and then at 100°C for 1 day to obtain vinyl sulfide Σ as a stereoisomer mixture in a yield of 80%. Ah, furthermore, 30%-H2O in AcOH at 40℃
Reaction with 2 gives a single product, 1, in 82% yield.

It has been confirmed from NMR spectrum analysis that 1 obtained as described above is E-integrated.

1: 'HNMR (CDCJs) 66.87 (d
q.

JM-N"15) IZ, JN-F-4,7Hz)
, 7.15 (d, JH-*=15Hz) 1'FNMR (internal standard: penzotrifluoride)
+0.7 ppm (d, JM-F-4, 7 Hz) Note that optical isomerization of 1 (in acetone, high-pressure mercury lamp) yields a mixture of 1 and its stereoisomer. The stereoisomer is (Z)-1- from NMR spectral analysis.
It has been confirmed that it is phenylsulfonyl-3,3,3-trifluoropropene.

Stereoisomer of l: 'HNMR (C'DCj!s) δ6
．． 23(d q, J x-h-12Hz.

J N-F-9Hz), 6.83 (d.

JR-9-12)1z) "FNMR-7.5ppm (d.

J N-F-9Hz) Next, when the above 1 is reacted with an active methylene compound,
The Michael addition product is obtained in high yield.

This reaction can be expressed by the following formula (where Nu-H is a nucleophile such as an active methylene compound).

CF2 For example, 1 can be converted to diethylmalone-1-1 in tetrahydrofuran at room temperature in the presence of a catalytic amount of NaH (0!%).
When treated with 6.3 for 5 minutes, adduct L3 was almost 100%
generate. The results are shown in the table below, including when other nucleophiles (eg acetophenone and its imine derivatives) were used. Note that this Michael addition reaction is preferably carried out under the following conditions.

Reaction temperature: 100-100°C Reaction pressure: Normal pressure Reaction time: 1 minute to several hours Solvent: Aprotic tetrahydrofuran (THF)
) etc.CO□Et hots isolated yield, 'B Next, the reductive desulfonylation of the Michael addition product obtained above will be explained. This desulfonylation reaction proceeds smoothly without any effect on the trifluoromethyl group as follows. For example, the acetophenone adduct 7b is dissolved in tetrahydrofuran-methanol at room temperature with Na
(Hg), 1-phenyl-3-trifluoromethylbutan-1-ol 8b is obtained in 70% yield and as a diastereoisomer mixture (1:1).

b qshi
~From each reaction mentioned above, the 1-phenyl- used
3,3,3-) Lifluoropropene 1 has a J phenylsulfonyl group in its molecule and exhibits high reactivity.

E. Examples Hereinafter, the present invention will be described in more detail with reference to Examples. However, the following Examples do not limit the present invention, and various modifications can be made based on the technical idea of the present invention.

Practical ■ (a) Synthesis of 1-phenylsulfonyl-3,3,3-1-lifluoropropene 10 3 Magazine 2゜3.3.3. -) Refluoro-1-phenylthiopropane Benzenethiol (13.95 g
, 127 mmol), KOH (8.5 g), ethanol (10 ml) and 3,3.3-1-lifluoropropene (15+j! at -78°C) for 4 days at 90
After heating at °C, the reaction mixture was poured into ice water and extracted with ether. The ether extract was washed with 1N-NaOH aqueous solution and brine, dried (MgSO4), and then distilled under reduced pressure to obtain 13.305 g (51%) of 3.

3: bp89-91℃ (17mmHg);
I R (NaC1) 1320'''1150cm-';
'HNMR (CDCj!z) δ2. lO~2.70
(2H, m), 3.00-3.20 (2H, m)+
7.20-7.50 (5H, m)i”F NMR
(CDCjl'z)+2.17 (t, J = 1
1.3Hz), M S m/e 206 (M”), 12
3゜109+ 7'L 69; H4gh res
solution MS Calcd, forCqHq
FsS+ 206.0376, Found 206
．． 037B.

1-Chloro-1-phenylthio-3,3,3-trifluoropropa 4 is: 3 (13,305g, 64.6n++sol)
, sulfuryl chloride (6,23[0) in carbon tetrachloride (6
After heating under reflux for 15 hours, the mixture was distilled under reduced pressure to obtain 14.046 g (90%) of 11.

11:bp107~110℃(20mn+Hg
), 'H-NMR (CDC1x) 2.7-3.2 (
2H, m), 5-37.3 to 7.8 (5H, m,
aromatic);”F-NMR(CDC1x)
0.43 (t, J=9.4 Hz); MSm
/e 240 (M”), 205.109° 1-chloro-1-phenylsulfonyl-3,3° 3-trifluoropropane 12:11 (14,048 g, 58.4 urtsol) in methylene chloride solution <200 ml) After adding metachloroperbenzoic acid (26 g) little by little under water-cooled stirring, the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, diluted with ether, and diluted with sodium thiosulfate solution and NaOH solution. After further washing with an aqueous NaCl solution, it was dried (MgSO4) and concentrated.The crude crystals were recrystallized with ethanol to obtain 9.515 g (60%) of 12.

12: m p 84.5-85.0°C;'HNMR
(CDC1z) 2.4-3.7 (2H, m),
4.8 to 5.05 (IH.

dd, J = 12 Hz, ~I Hz),
7.6 to 8.2 (5H.

m);”F-NMR (CDC1s) 0.55 (t
.

J -9,4Hz); M S m/e 272
(M”), 141.77; Highreso
lution Ms Calcd, for Cq
HaCI F30.5271.9885. Faun
d 271.9896.

1-phenylsulfonyl 3,3,3. -Trifluoropropene 1: 12 (3,604 g, 13.22a + moj of methylene chloride solution <20 tel) under water-cooled stirring, 1
．． 8-Diazabicyclo(5,4,0)-7-undecene (2.5 g) was slowly added dropwise. After the dropwise addition was completed, the mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ether. After washing the ether extract with NaCl aqueous solution, drying (MgS
O,), and concentrated under reduced pressure. The obtained crude crystals were recrystallized from n-hexane to obtain 2.61 g (84%) of 1.

1: m p66-66.5℃; IR (K Br
) 1325.1140°960cm-';'HN
M R (CD Cl 3) δ6.87 (d q,
Jg-w”15Hzt JN-F-4,78Z),
7.15 (d, JN-11-15Hz), 7.5
~8.1 (5H, m) ;”F NMR+0.7
(d, JH-r"'4.1 Hz); Anal,
Ca1cd, for C5HtF*OzS C45
,76°H2,99,F24.13. S13.57. F
ound C45,99,H3,04,F24.01
．． S13.42.

l-Phenylsulfonyl 3,3.3. -) Benzenethiol (25.2 g) in a stainless steel reaction tube
, NaOH (15,3 g) and 1-chloro-3,3
゜3-Trifluoropropene (44++j! at-7
8℃), ethanol<40℃m 1 ) for 3 days, 10
Heated to 0°C.

The reaction mixture was poured into ice water, extracted with ether, and dried (Mg
SO4), then distilled under reduced pressure, 3. 3. 3-1-Lifluoro-1-phenylthiopropene 5 t-38,70
2g (83.4%) obtained.

A: bp78-80℃ (9mmHg); "F-NMR
(CDC13) 2.0 (d d, J = 7.5
Hz, J -2,8Hz), +10.0 (d
, J = 7.5 Hz), Q (38,702
g) was dissolved in acetic acid (75 tal) and stirred under water cooling.
30% hydrogen peroxide solution (47a+I!, 450m
mol) was added dropwise.

After completion of the dropwise addition, the solution was stirred at room temperature for 1 day and then at 60°C for 1 day.
After adding dimethyl sulfide (5 ml) to the reaction mixture,
It was concentrated under reduced pressure, diluted with water, and extracted with ether. Wash the ether extract with NaOH aqueous solution and NaCl aqueous solution,
Dry (MgSO4), concentrate under reduced pressure, and recrystallize the obtained crude crystals from n-hexane to give 30.2 g of 1 (80%
)Obtained.

Synthesis of (bl 1-)lifluoromethyl-2-phenylsulfonylethylmalonic acid diethyl ester in tetrahydrofuran under argon flow (4mffi)
, Sodium hydride (2 nag) and diethyl malonate (128 mg) were stirred for 10 minutes under water cooling, and 3.
3゜3-Trifluoro-1-phenylsulfonylpropene 1 (113 mg) was added and stirred for 10 minutes.
The reaction mixture was poured into 10% hydrochloric acid and extracted with ether.

The ether extract was washed with NaCl aqueous solution and dried (MgS
O4) After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, and 190+eg (quantitative) of 7a was obtained from the portion eluted with n-hexane-ethyl acetate (8:1).

7a: Colorless oily substance; IR (NaCl) 1760
゜1740am-';' HNMR(CD CI
61.2~1.4 (6H, m), 3.3~
4.4 (8H, m).

7.5-8.1 (5H, m);-9F-NMR
(CDC1,) +4.5 (d, J-8,7H
z); MSa+/e 351 (M'-Eto), 3
05,255,199.125 ;High reso
lution MS Calcd, forC+aH
+*FsObS396.0853. Found 3
96.0865-(C)1-phenylsulfonyl-2-
Synthesis of trifluoromethyl-4-phenylbutan-4-one Sodium hydride (5 mg) and acetophenone (350 mg) in tetrahydrofuran C (5 ml) and 2-methyl-2-propanol (5 ml) under an argon atmosphere.
) was stirred for 10 minutes under water cooling, then 1 (237 mg
) and stirred for 20 minutes, the reaction mixture was poured into 10% diluted hydrochloric acid and extracted with ether. ether extract with N
After washing with aCl aqueous solution, drying (MgSOa), and concentration under reduced pressure, the residue was subjected to silica gel column chromatography, and the obtained crude crystals were recrystallized from ethanol from the part eluted with n-hexane-ethyl acetate (8:1). 7bl), 216.4 tags (60%) were obtained.

7b:mp130℃; IR(KBr) 1680
cm-';' H-N M R (CD Cl 5)
63.3-4.0 (5H.

m) ,? -4~8.2 (10H+m): 'Drop F-NMR (CDCfs) +7.2 (d, J=
7.7 Hz) iMS ya/e 356 (M”
), 309,251,215.105 ;Ana
l, Ca1ccL for CrtH+5FsOsS,
C57,30,H4,24,F 15.99. S
9.00; FoundC57,1? , H4,18
, F 16.10. S 8.92.

Under a stream of ground argon, diisopropylamine (240 μl and n-butyllithium (
1,67 m ■ oj under dry ice-acetone cooling,
After stirring for 10 minutes, a solution of imine 6 G (340 mg) in tetrahydrofuran (110) was added and stirred for 20 minutes.Next, a solution of 1 (124s+g) in tetrahydrofuran (210) was added and after stirring for 15 minutes, the reaction mixture was poured into ice water. The ether extract was washed with an aqueous NaCl solution, dried (MgSOn), and concentrated under reduced pressure. 10% HCl was added to the residue, and the mixture was diluted with 10% HCl at room temperature.
After stirring for an hour, it was extracted with ether.

The ether extract was washed with NaCl aqueous solution and dried (MgS
After O4), the residue was subjected to silica gel column chromatography, and n
From the -hexane-ethyl acetate elution portion, 157.8 sag (85%) of 7b was obtained.

Group 11 (al) Desulfurization reduction reaction of Michael addition product 1-phenyl-3-trifluoromethylbutan-1-ol 8!?: 0 Mi Plane Under an argon atmosphere, phosphoric anhydride in tetrahydrofuran (410 -Sodium (110
s + g), 7 b (66,5B), 5% sodium amalgam (1,2 g) was stirred at room temperature for 2 hours, then
10%-HCl was added to the reaction mixture and extracted with ether. The ether extract was washed with NaCl aqueous solution and dried (M
The residue was subjected to silica gel column chromatography under reduced pressure and t1MtR1, and from the fraction eluted with n-hexane-ethyl acetate (10:1), 19 mg (46%) of 8b was obtained.
Obtained as a diastereomer mixture.

8b: Colorless oily substance; IR(NaCl) 335
03-';'H-NMR (CDC13) δ1.13
(1,5H,d.

J = 7 Hz, -CH3for one dia
stereos+er)+1.17(1,5H,d,
J = 7 Hz, -CH3for another
diasLereomer), 1.33-2.70
(4H, m), 4.53-4.90 (I H
, m, nCH-0-), 7.42 (5H.

s, Ph) i”F-NMR (CDC1s) + 10.5 (
for one diastereoser)+ +1
1.0 (for another astereo
er) *(bl D tels -A 1der reaction bicyclo(
2,2,1) -2-) Lifluoromethyl-3-phenylsulfonyl-hept-5-ene 13: Under argon stream, L (594 mg, 2.52i+mo
l) and TH of cyclopentadiene (0,5sJ?)
After stirring the solution for 1 hour at room temperature, it was purified with silica gel column chromatography to obtain n-hexane-ethyl acetate (
8: 1) From the elution part, 480i + g of 13-1 (
63%).

129s+g (17%) of 13-2 was obtained.

May%-U/13-1: Colorless crystal; m p 106-107°C (f
rom nl-~2--7 monohexane); I R (K Br) 1300.1200.1140cm
-';'H-NMR (CDCj!,) 61.5
8 (IH, d, J-9Hz).

2.16 (I H, d, J -9Hz), 3
．． 00~3.55 (4H, m), 6.30 (2H
, b s), 7.55-8.20 (5H, m),
”F-NMR (CDCfs)+2.17 (d, J
=8.7 Hz); MS ll/e 302 (M”)
.

237+ 177.161; Anal Calcd,
for C1nH+3FsOzSC55,62,H4
, 34, F1a, 85. S 10.60; Foun
dC55, 72, H4, 3B, F 1B, 94. S
Lo, 90°: colorless crystal; m p 115-11
6°C (fros n-hexane); IR (K Br) 1300.1200.1140
>-';'H-NMR (CDCI,) 61.4
2-1.80 (2H.

m), 2.43-2.85 (IH, m),
3.15-3.40 (2H, m), 3.65-3.
80 (l H, d d, J=6 Hz, 3.5
Hz), 6.45 (2H, b s), 7.50
~8.10 (5H, m); 'Drop F NMR (C
DCJs) + 3.7 (d, J = 8.7 Hz);
MS s+/e 302 (M”).

237+160; Anal, Calcd, f
or C+4H+sF 5etsC55,62,H4,
34, F 1B, 85. s 10.60; Found
C55, 61H4, 32, F 1B, 9T, S 1
0.49° 3-trifluoromethyl-4-phenylsulfonylcyclohexanone 15: 1 (104 mg, 0.49°) in a Pi L/7 glass tube.
44 mmol) and 2-trimethyl-siloxy-
1,3-Butadiene 14 (180 mg) at 110°C
After heating for 4 hours and a further 3 hours at 130°C, the reaction mixture was dissolved in 2I11 ethanol and 10% HCj! (
1sJ) and stirred at room temperature for 1 hour. The reaction mixture was extracted with ether, the ether extract was washed with an aqueous NaCl solution, dried (MgSO+), concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography. From the n-hexane-ethyl acetate (5:1) eluted portion, 92.5 mg of the base was extracted.
(68.2%) was obtained.

Colorless oily substance: IR (KBr) 1710 (Jl-I; 'H-NM
R(CDClx>62.10 ~3.85 (8H,
m), 7.70-8.25 (5H, m);
”F NMR (CDCI, )+5.67 (d,
J = 9.4) 1z); MS m/e 307
(M”+1), 288,165.14
3;High resolution M 5Cal
cd, for C+sH+nF*OsS (M”+
H) 307.0614. Found 307.06
0? .

5-Trifluoromethyl-3-methyl-4-phenylsulfonylcyclohex-2-en-1-one: Under an argon atmosphere, 1 (2.82 g, 12 mmol
) and 2,4-bistrimethylsiloxy-1,3-
After heating and refluxing a solution of pentadiene 16 (3.50 g, 14 + moj in toluene (20 ml) for 55 hours,
Ethanol (120ml) and 3. to the reaction mixture.
The reaction mixture was diluted with water and extracted with ether. The ether extract was washed with NaCl aqueous solution and dried (MgSOJ
The residue was purified by silica gel column chromatography to obtain 2.97 g (78%) of K from the fraction eluted with n-hexane-ethyl acetate (4:1).

17: Colorless crystal; m p 109-110°C (fro
mcyclohexane); I R (K Br) 1675.1640 country-';
'H-NMR (CD C1s) 62.00 (3
H, s, CH3>.

2.56 (I H, d, Jgem-19Hz, CFs-
C-CH-CO) 2.89 (I H, d d,
Jgem-19Hz, J-7,2Hz.

CF3-〇-CH-Go), 3.30-3.55 (I
H.

m), 4.10 (L Hls , >CHS 0x-)
, 6.20 (I H,s , olefi*fc),
7.60-8.00 (5H.

m) i”F NMR (CDC13) + 7.0 (d.

Claims (1)

[Claims] 1 General formula: ▲ Numerical formulas, chemical formulas, tables, etc.▼ [However, R_f is a fluorine-containing aliphatic group; R^1 is an aliphatic or aromatic group; R^2 is a hydrogen atom, group or aromatic group, hydroxyl group, alkoxyl group, amino group or alkylamino group; R^3 and R^4 are hydrogen atoms, aliphatic or aromatic groups, cyano group, carboxyl group, -COOR^7 group or -CONR ^8R^9 group (R^7 is an aliphatic group, R^8
and R^9 is a hydrogen atom or an aliphatic group. ); R^5 and R^6 are hydrogen atoms or aliphatic groups. ] A fluorine-containing sulfonyl compound represented by: 2. The fluorine-containing sulfonyl compound according to claim 1, wherein R_f is a perfluoroalkyl group having 10 or less carbon atoms. 3 R^1 is an alkyl group or phenyl group having 1 to 10 carbon atoms, R^2 is an alkyl group or alkoxyl group having 1 to 10 carbon atoms, or a phenyl group, or The fluorine-containing sulfonyl compound described in item 2.