JPS5993081A - Novel diketopiperazine derivative, its preparation and plant growth regulating agent containing said compound - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (R is H, lower alkyl, benzyl or acyl). EXAMPLE:Cyclo(Dallyp-D-Pro). USE:A plant growth regulator having sprout promoting, growth promoting and root promoting activities. It is useful also as a synergist for plant hormones, agent for inducing a seedless fruit, etc. PROCESS:The cyclo(Hyp-Pro) and cyclo[Hyp(OR)-Pro] of formula I can be prepared by heating proline and hydroxyproline derivative of formula II in a solvent such as ethylene glycol or in water. When the product is a mixture of steric isomers, it can be separated easily into individual isomers by fractional crystallization and column chromatography.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a novel diketopiperazine derivative, a method for producing the same, and a method for preparing the active ingredient of the diketopiperazine derivative.
and drugs.

In recent years, the food problem is expected to become more acute, and efforts are needed to secure and even increase the production of agricultural products, and much research is being conducted. We believe that it is also important to minimize the production loss of agricultural products due to abnormal weather, etc., and for example,
We have been searching for compounds that can normalize the growth of so-called so-called so-called so-called so-called so-called so-called sludge-like agricultural crops.

As a result, the present invention provides novel dandruff 1. The present invention was completed by discovering that piperazine derivatives can be used in plants such as η-Nagao Takusakugawa.

The object of the present invention is to provide a novel zig-1-piperazine derivative, a method for producing the same, and a plant growth activator containing the compound as an active ingredient.

The compound of the present invention is represented by the following general formula (I).

○ ○ (In the formula, R represents hydrogen, a lower alkyl group, a benzyl group, or an acyl group.) In the compound of the present invention, R is hydrogen; a carbon number of 1 to 1, such as methyl, ethyl, butyl, butyl, pendel, etc. 5 lower alkyl group, benzyl group; A1! chill, propimenyl,
Acyl groups having 2 to 5 carbon atoms such as butyryl and pentenyl can be used.

1; J, F, ・General formula (1) is converted to Schiff Ll (Hyp-P
ro) (if R is hydrogen) or Schiff o (IIyp
fOR)-Pro] (when R is throat rigging ■) and Table 1
0 Note that 1lyp represents hydroxyproline, Pro represents proline, and allyp represents that the bridgehead hydrogen and the OR group are trans isomers. These amino acids are D-form, 1
7 body, I) L mixture can be used.

For example, Schiff I' (L-1(Vp(OR)-L-P
ro) The compound of the present invention can be synthesized by various methods, including, for example, the following method.

(Synthesis method 1) Proline and the hydro↑-enzololine derivative represented by the general formula (n) (I? has the same meaning as in the above general formula (1)) are mixed in a suitable solvent, such as Godi. The compound of the present invention Schiff 11 (
II 5'l'l-Pro) and Nkuro White 1 yp
(OR) -rroll is synthesized.

/1; When the acid is a mixture of stereoisomers, each stereoisomer (') can be easily separated by fractional crystallization or Kanno chromatography. The configuration of the group is based on the general formula (I
I) (7) 4 (iγ's 017) Defined by the Zetsuke 1 arrangement of fortune telling.

In addition, Schiffl:' (P ro-P
ro), Schiffl:I (II yp-II yrl>
and cyclo(11yp (Oil) -II yp(0
11)) can be hydrolyzed into amino acids into 4 crystals, and there is a reprint version of 1-+Jil.

(Synthesis method 2) The 4 invention compounds are synthesized according to the general formula (Ill) or -
・General K (IV) Cyclization reaction of dipebudi 1' derivative or its esral derivative shown in C4) can also be carried out by (IT, I)
(1,V) (wherein R is the general formula (1,
), and R' does not represent hydrogen, allyl or lower alkyl group (synthesis method 3) Among the compounds of the present invention, alcohol (one or lower alkyl group) and hexyl compound ( The alcohol H? is hydrogen).

On the other hand, the pendyl mexi form is converted to the alcohol form by catalytic reduction, and the acyl form is converted to the alcohol form before hydrolysis. j i
It is possible to

(Di4!1 reaction) Each stereoisomer of the compound of the present invention has the following
+i relationship is established, and using this relationship, other three-dimensional layers 11
Can be converted into one.

The desired purpose can be achieved by heating in a protic solvent such as water or ethylene glycol. In addition, in a suitable solvent such as alcohol,
It may also be treated with a base such as sodium alkokino 1'.

Examples of the production of the compounds of the present invention are shown below.

Example 1 85 mg of proline') and 655 mg of 4-R-hydroxyproline were added to 31 TIQ of ethylene glycol.
-III I 8 (Add flV at 1°C for 3 hours 6 After distilling off the solvent under reduced pressure, add a small amount of water and prepare sub-t1 product 1) (
The aqueous layer was dried under reduced pressure, the residue was dissolved in chloroform, and ethyl acetate was added to precipitate the secondary product Hyp-IIyp. The filtrate was dried under reduced pressure, and then dissolved in a mixed medium of chloro11porno/methanol (9/l).
The sample was treated with a chromatographic J7 chromatography (interlayer using the same solvent). The solvent was distilled off from the first fraction and white crystals of Tsuku' (L-II yp -L-Pro) were obtained.
30 mg, and then the solvent was distilled off from the obtained fractions to obtain white crystals 19 (1 mB) of cyclo(D-allyp-11-Pro).

Cyclo(L-1-1yp L-Pro)m, p,:
141 142℃ Cα)28−− +34.4°(c=I, MeO
ll) I) NM+? (CDCl2): Figure 1 Cyclo (D
-allyp-11-Pro)m,p,: 17
4-175 °C (tY) +3 -'-90-11
' (c-11M e O1+)Nt11ton (C
D(:+3): 142 The following compound was obtained in the same manner as shown in the figure.

Tsuk+1(1)-It yp-IL Pro)m, ρ
,: 14+-142°C (α), -+ 134.0° (c = l,
MeOII) Nth+1 (CDCl2>: Figure 1 cyclo (1, -allyp-1, -Pro) fi
,p,: 175-176°C [α),, ---90,4° (c-1, Me(beating NMII (CDCl2): Figure 2 Example 2°N-cal;l Sabenzoxy L-proline 250mB
Tori++ Ruformic acid ethyl 120 mt+ and triethylamine If (1 mH TIIp50m, fl III-
After incubating for 30 minutes at 5°C, 150 mB of L-human+:+-t-fn') methyl ester was added.
1° of solution was added. After stirring at 0° C. for 5 hours, the mixture was washed several times with water, dried over anhydrous sulfur, and then dried under reduced pressure.

Dissolve the residue in methanol and add 10m of 10% Pd-C catalyst.
Catalytic reduction was carried out in the presence of B under normal pressure of hydrogen for 6 hours. After filtering off the catalyst, it was dried and recrystallized from ethyl acetate to give cyclo(L
-Hyp-L-Pro) conclusion! 95 mg was obtained.

Similarly, cyclo(L-11yp-1,-Pro)
I got it.

The physical properties of both products were consistent with those obtained in Example 1.

Example 3 Cyclo (L-11yp-L-Pro) 500mg
was stirred at room temperature for 3 hours in a mixed solvent of acetic anhydride/pyridine (8Tnp/2yni'). The solvent was distilled off under reduced pressure and the residue was crystallized from ethyl acetate to give cyclo(1-II
yp (OAc)-L-P ro, ) crystal 54 (1 m
(I got H.

m, p, 199-200°C8 (α),, −110,4° (c −1, MeO
ll) NMR (C11CI, )・ Compounds LJJ and F were obtained in the same manner as shown in FIG.

Tsuku l: I CD-II yp (o to c) -11-
Pro) m, p,: 19B-199'c (α)28=1. 109.9° (C= ],
He'1l)I] NM+n (CIICI ρ: Figure 3 Cyclo (
1,-allyp(OAc)-L-Pro)m,p,
: 129 130°C [α)28=-G1. ! 3° (c = 1, 6eO
11) 1) NIII (CDCI): Figure 4 3 Cyclo CD-allyp(O to c)-D-Pro)m
, p,: 130-131 °C [α) =
+62.0° (c = 1, Merit) 1) NMII (C11CI): Fig. 4 Example 4
゜Sif 1no (ILI[yp-11-Pro) 42
0 mt+ and Na1l 50mg anhydrous TIIF 10
React for 1 hour at 0°C in 0-0°C.
430 mg of El was reacted in the same solvent at room temperature overnight. After distilling off the solvent, it was washed with water, dried over anhydrous 1-lium sulfate, and crystallized with ethyl acetate to give the following compound on il.
Zoko.

Schiff 17 (L-II yp (0 gate e) - L-P ro
] Mark, p,: 139-140'c8 [α]1. --103.4° (c = 1, M
eOII) Nton (C11CI): Fig. 5 Shift t' CD-11yp (Omon e)-D-Pro)
m, p,: 139--140°C [α)28= +103.2° (C= l, Me
OII) I) NMII (CDCI3'): Figure 5 Cyclo (L
-allyp(OMe)-1,-Pro) oil ((Y128=-74,2' (c, = I,
Meoll)r) NMR (CtlCI3): Figure 5 Cycloco CD
-al15'll(OMe)-11-Pro: ] Oil 8 [α) = 174.5° (c = I, il
eOII) 1) NMR (CtlCI3): Figure 6 Example 5゜ In the same manner as in Example 4, anion A and benzylpro iF
By avoiding the reaction, the following compound F was obtained.

Cyclo (L-II yp (Hz l) -L-P
ro) m, p,: 108 109°C [α)28=-102,6° (c = 1, il
eOII) I) NMI (CHI] CI 3): 7th
Figure Schiff 1. 'l (ILII yp(OBzl)
-D-P rolm, p, : I (17--108
°C[α]"' -4102,1° (c = 1,
Meoll) 1) NMR (CtlCI): Figure 7
L-allyp(OBzl)-l, -Pro) 411-like substance 8 [α) −-20,0° (c = 1, Me
Oll) I) NMR ((:DC+3): !I ■Fig.
Il) Ding] N11ll (CDCI3): Figure 8 Example 6゜Cyclo(IIIVI) Pro) was heated in about 3 times the volume of ethylene glycol at 1'C for 3 hours. After the solvent was distilled off under reduced pressure. The stereoisomers were isolated by fractional crystallization of the residue or by silica calanochemistry.

That is, from Schiff D (4(R)-II yp-P ro), cyclo(L-It yp-L-P ro) and cyclo(1Lallyp-1]-1) ro) are obtained,
Schif' (4(S)-If yp-Prolgara,
Cyclo(1)-Hyp-D-Pro) and Schiff+:
+ (1,-ally+'-1-Pro) was obtained.

Similarly, Schiff I' (4(It) Hyp (OMe
)-Pro) gives cyclo (L-If yp(O
Me)-L-P rol and Schiffr+ (11-all
yp(OMe>-11-P ro) is cyclo(4(S
)-IT yp(OMe)-Pro) to cyclo(1)II yp(OMe)-D-Pro) and Schiff I7(L-811yp(OMe)-1,,4" ro)
) wall cyclo (4(1υ-shou1yp(08c)-P
ro) to cyclo (L-II yp (08(
-n-L-Pro ro'J and Schiff 141 CD-all
yp (O to c)-1)-Pro) is cyclo(4(
From S)-II yp (08c)-Pro), cyclo (l]-II yp (to Ll8)-〇-Pro'
J and Schiff I'ff (L-allyp(O to c)-1
, -Pro) is tsukl:l [4(II)-II
yp(OBzl) -P roll Garara, SokushiJ
(1, II yp(OBzl) −1, −Pro ro) and Schiff T: + [I] −allypUIlzl) −I
L r' ro) is cyclo(4(S')-II yl
)(OBzl)-P ro), cyclo(Dll
yp(OBzl)-D-Pro) and Schiff I7[],
allyp(Ollil)-L-Pro) were obtained, respectively.

The physical properties of all the products obtained were the same as those described in nj+.

Next, an example of the plant growth regulating action of the compound of the present invention will be shown.

(+, ) Germination promoting effect on rice A germination test was conducted using paddy rice (Zennanfu) that was produced in 1975 and stored in a cold storage at 4°C. All tests were conducted in August 1982.

A 61 paper soaked with water-soluble γCζ (+-6M) of the test drug was placed in a pellet plate as a germination bed, and 100 Type 5 seeds were placed in a dark place C experiment. For each group, three germination beds were prepared and the average value was determined.
±1° (and 30”-1°C) was selected. As a comparative drug, 1-megluhydan Iyne with optimal conductivity (+×IO=M) was used.

jKo;+zt+ Y, III”]1. Δgr, C
I+emSoc, , japan, 22.238 (1
958)1 Table I shows the results of the germination test at 20°C, and Table 2 shows the results at 30°C. No deterioration was observed.Germination vigor was 2 (5% lower than germination at 1°C).
．． When the temperature was 50°C and 30°C, the cumulative germination rate was expressed as 2.511 eyes.

Table 1 Test drug Germination force (Z) Average germination 11 beds (
Yen) Control (Earning W/Wed) 35.0±2.1
6.08+(+, (141-methylhita:/toy7a)
47.7:l:2.7 5.84'(1,0111]) t+(+, -11yI'l-1-Pro)
53.8:! , : 2.6 5. (iG:!: 0.
08b) Tsuk11(Ding)-allyp-1)-Pro) 6
3. (1:!: 1.2 5.52:! (1,03sik, [1, -'llyp(OMe)-LJroll))4
0.0:! :2.9 6.12-,! 0.05■]) cyclo[■, -11yp(OAc)-L-Prol
45, 7±4.1 5.1171: 0.07-4
-6 - -a) IXl,
OM, b) 1. x], OM ”mean value-I S,
E.

Table 2 Test drug Germination vigor (Z) Average number of germination 11 (
II) Sentence = lll/+ (pl + < IVj water) 44.3-
t2.62.901! 20, 021-Methyl Kamidan 1-
Ina) 63.0±2.5 2.771 (1,041
)) Cyclo(L-Hyp-], -Pro) 58.3
-14.5 2.71', -0.03 sikry (D-
allyp-D-Pro) b) 65.0±3.6 2.
71±0.02b) Tsukut? lL-11yp((IMe)-L-Prol
58. Q±2.0 2.77±0.02sikt71
L-11yp (OAc)-1, -Propb)58
．． 7±1.8 2.75±0.028) ON, b
) ] XIOM ”Mean ± S, Ii.

The optimal germination temperature for rice is 30°C, and at this temperature (Table 2
), the germination ability and germination vigor of the control plot showed normal values, indicating that the germination vigor of the test seeds was close to the maximum value. On the other hand, in the low-temperature Suleless F (20°C1 Table 1), the germination vigor was weakened, and the average germination rate in the control plot was about 2 i'f of the normal value.
This shows that the starting force has decreased by 1'.

In both cases of 20'C and 30°C, the germination vigor and average germination were 6 +113! Both the compounds of the present invention showed a significant germination-promoting effect at a concentration of 10M.Especially, the effect at 20°C was more pronounced. It is more effective against plants in a sullaceous state.

(2) In the experiment of rice growth promotion effect (1), 25 grains of seeds Y that germinated between 21] 1 and 311 seeds were randomly selected and placed in 781 m of the corresponding test medicated water for hydroponic use. Transplant it to the bed placed in C and keep it in the dark for 6 days.
Cultivated. Experiments were conducted at 30±1°C.

As a result, there was no difference between the control group and the l-methyl dan-1-yne used as a comparative drug even at its optimum concentration of lXl0M.
On the other hand, in the group treated with the compound of the present invention, the test drug concentration I
-6M concentration significantly promoted seed root growth. In addition, the compound of the present invention is useful and unique in that it does not act on the above-ground part and therefore does not cause the above-ground part to become elongated.

An example of the results is shown in Table 3.

Table 3 Test drug Seed root (<: m) k[
Upper part of the mouth (('') control (steamed ξ°l water) 9.3±1.47.
4:! :0.8a) 1-Methylhytantoin 9.8 to 2.3 7.7:
l-0,7b) Tsuktl (L-llyp-1-Pro) 12
．． 3±1. ? ! 7.3' 0. (ib) Tsukt+ (1), allyp I)-PI-(,1
)] 3.3±1.5 6.9:! -0,51
]) Cyclo(1-1lyp□Me)-L-Prol
B, g±2.0 6.9': 0.71]) Tsuku +: +11. -11yp (08C) 1. -Prn
lg,4±1.3 7.24-(1,fi) As is clear from the results above, the compound of the present invention has a useful plant growth regulating effect, and therefore, for example, it has a germination (jQ promoter, /L It can be used as a growth promoter and a rooting promoter, and can also be used as a rooting promoter.
Xist), as an inducer for seedless fruits, etc. (Also, its use is not expected.

[Brief explanation of drawings]

Figure 1 shows TsukO(1,, -[1yp -L-P ro)
and N of cyclo(ll-11Vll-11-■'ro)
It is an MR diagram. Figure 2 shows the NM of cyclo(1-allyp-L-Pro) and tsuku l-1(1)-allyp-D-Pro).
This is an R diagram. Figure 3 shows cyclo(1-II yp (OAc)-L-P
ro) and Tsuku t1 (D-11yp(08c)-11
-Pro) is an NMR diagram. Figure 4 shows cyclo(L-allyp(OAc)-1,-1
)ro) and cyclo(II-allyp(08c)-l
)-P rol N M Rl'M. Figure 5 shows Tsukuu (1-It yp (OMe)-1,
-, Pro) and cyclo(D-Hyp(OMe)-1
1-Pro). Figure 6 shows Tsuk+:+ (1-allyp(OMe) river,
-Pro) and Tsukuno [11allyp((IMe)
-Df)ro) is an NMR diagram. Figure 7 is Tsuk+:+ (Lityp(OBzl)-1
-Pro roll and tsuk1' (IL II yl+(
It is an NMR diagram of ORzl)-llPro). r (< 8 Figures are: I
zl)-1-Pro) and tsuk1:' (lLally
FIG. 3 is an NMR diagram of p((ll171)-IL4)ro). Agent (6891) Patent Attorney Sababe Murayama Figure 2 Figure 3 Notebook Figure 4 Figure 5 Figure 6 Figure 7 Iris Figure 8

Claims (2)

[Claims] (1) A novel piperazine conductor represented by the general formula (1). ○ (In the formula, R (J hydrogen, lower alkyl group, Hensyl J, U
, or represents acylfu. ) (2) - In producing a novel diketopiperazine derivative represented by the general formula (+), (wherein 1? does not represent hydrogen, a lower alkyl group, a Hensyl group, or an acyl λ, ) (a) Reacting proline with a hydroxyprosone derivative represented by the general formula (■1), (R has the same meaning as the general formula (1) above!!), or (b) - The dibebutylic derivative represented by the general formula (lli) or the general formula (IV) is cyclized (Ill, ) (IV) (1≧
The general formula (1) is characterized in that O; 1 - General formula (+> has the same meaning, R' is hydrogen, -ryl J, (or represents a lower alkyl group) A method for producing a novel diketopiperazine derivative represented by the formula (;3) A plant growth regulator containing a novel diketopiperazine derivative represented by the general formula (1) as an active ingredient. ○ (In the formula, R is hydrogen , lower rlkylno & Hensyl group,
or -rsilno, (not expressed)