JPS5815997A - Novel tylosin derivative - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formulaI[R1 is amino, mono-, or di-lower alkylamino, a group shown by the formula II (n is 2-20); R2 is H or OH; R3 is aldehyde group which may have a protecting group]. EXAMPLE:23-Deoxy-23-ethylamino mycaminosyl tylonolide shown by the formula III. USE:An antibacterial agent. Having high antibacterial power than tylosin, mycaminosyl tylonolide, etc. A dose of 10-1,000mg/time is medicated orally(parenterally). PROCESS:A compound shown by the formula IV (R3' is an aldehyde group with a protecting group; X is halogen) is reacted with a compound shown by the formula R1-X (e.g., ethylamine, etc.) in an organic solvent such as preferably THF, etc., and, if necessary, the aldehyde-protecting group is eliminated.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to Tylosin derivatives. Tylosin has a 16-membered ring lactonomoiety and a 3-membered ring.
Two constituent sugars [mycarose (mycarO8e) *
16 consisting of mycinose and mycaminose]
Member ring macrolide system.

It is an antibiotic. By studying its acid hydrolysis.

The presence of the lactone moiety and mycaminose was found to be important for the expression of antibacterial activity, and mycaminosyl silonolide or a compound iodinated at the 23rd position is known (Special Publication No. 47-18633 2 Japan Pharmaceutical Sciences 100th Annual Meeting). In particular, it has been reported that the latter compound has significantly increased antibacterial activity compared to tylosin.

The present inventors have discovered that mycaminosyl quilonolide 23
The present invention was completed by discovering that the antibacterial activity is further enhanced compared to known similar compounds such as derivative tylosin and mica-minosyl tylonolide, which have an amino substituent introduced therein.

The tylosin derivative of the present invention has the general formula [wherein +R1 is an amino group, a mono- or di-lower alkylamino group, or 2-N)R2)n (in the formula).

n represents an integer from 2 to 20. ), R2
represents a hydrogen atom or a hydroxyl group, and R3 represents an aldehyde group which may have a protecting group. ] This is a new compound represented by

Examples of the mono-lower alkylamino group include methylamino group, -ethylamine group, isopropylamine group, inbutylamino group, and hexylamino group, and examples of the di-lower alkylamino group include dimethylamino group.

Diethylamino group, dipropylamino group, dibutylamino group, diisobutylamino group, dihexylamino group, N
-Methyl-N=ethylamine group, N-methyl-N-isopropylamino group, N-methyl-N-hexylamino group, N-ethyl-N-butylamino group, N-ethyl-N-
Examples include hexylamino group, N-propyl-N-bentylamino group, and N-bentylamino group.

The antibacterial activity of the object compound [1] of the present invention is shown in Table IK.

In the present invention, the target compound [I] has the general formula (wherein, the phantom is an aldehyde group with a protecting group.

X represents a halogen atom, and R2 represents the same meaning as above.

) and a compound represented by the general formula % (1) (in the formula + RH represents the same meaning as above).9 Then, if desired, the protecting group of the aldehyde group is removed. can do.

The aldehyde group with a protecting group is one protected in the form of an acetal or thioacetal, and specifically, dimethyl acetal, diethylacetal, and diethylthioacetal.

Ethylene acetal, ethylenethioacetal.

Examples include probile/acetal and those having a substituent such as a methyl group.

The reaction between compound [n] and [11 is performed using tetrahydrofuran,
Acetonitrile, dioxane, dimethylformamide,
It is preferable to carry out the reaction in an organic solvent such as dimethyl sulfoxide at room temperature or with heating.

The protective group for the aldehyde group can be removed by treatment with a mineral acid such as hydrochloric acid or sulfuric acid or an organic acid such as trifluoroacetic acid or trichloroacetic acid in the presence of water.

The target compound [I] is prepared as a tablet using a conventional pharmaceutical carrier.
It can be prepared into powders, granules, capsules, injections, etc., and administered orally or parenterally. The appropriate dosage is 10 to 1000 mg administered 1 to 4 times a day.

Next, the present invention will be explained in more detail with reference to Examples.

Example 1 (a) 23-deoxy-23-iodo mycaminosyl quilonolide 110 mg of diethyl acetal
．． The mixture was dissolved in 2 mt of anhydrous acetonitrile, 63.5 mg of ethylamine was added thereto, the mixture was reacted at 80C for 5 hours, and then concentrated to dryness under reduced pressure. The residue was dissolved in 5.5 mz chloroform + 2 m4 saturated aqueous hydrogen carbonate solution and washed once each with saturated aqueous sodium sulfate solution.

After drying over anhydrous sodium sulfate, it was concentrated to dryness under reduced pressure.

The residue was transferred onto a 1 g silica gel column using a solvent system of chloroform-methanol-ammonia water (15:1:0.1
) to obtain 23-deoxy-23-ethylamino mycaminosyl tylonolide dieteracetal. Yield 71.4 mg (yield 72.5%
) Physical and chemical properties (1) Nuclear magnetic resonance spectrum (CD CJ3) δ(p
pm) H number form J (ratio) Attribution 2.5
5 6's 3'-NFi
lie22.77. 23-N
HCH2CH3~3.52 "
CH(OC3CHa435 1 a,',2'7
．． 5 H1'~4.8 2 m X2
Has, H20 (11) Colorless amorphous solid (reprecipitated from dichloromethane-〇-hexane) (iiD Elemental analysis value (as C37H66N2010) 63.31 9,23 3.98 (iv)
Cα] sweet + se 3° (c 1.0, CHces)
Example 2 30.5 mg of 23-thioxy-23-ethylamino mycaminosyl quilonolide diethyl acetal was dissolved in Q, 6 mt of acetonitrile +1. ．． 3
0.mt. An aqueous IN hydrochloric acid solution was added, and the mixture was reacted for 60 minutes to remove diethyl acetalization.

After the reaction was completed, 15 mg of hydrogen carbonate (IJ) was added to the two reaction solutions, and the mixture was extracted three times with +3 mt of chloroform.

The chloroform layers were combined, washed twice with a saturated aqueous solution of sodium sulfate, dried over anhydrous sulfuric acid, and concentrated to dryness under reduced pressure. The residue was dissolved in 4 g of silica gel (Kies
elgel 60,230-400 mesh) column.

Solvent system Chloroform-methanol-concentrated ammonia water (1
Chromatography was performed at a ratio of 2:1:0.1> to obtain 23-deoxy-23-ethylamino mycaminosyltylonolide.

Yield: 24.0 mg (yield: 89 cm) Physical and chemical properties (1) Nuclear magnetic resonance spectrum (CDC43) δ (pp
m) H number form J (seven) Attribution 2.5
4 6 s 3'-NMe22
, B 023 NHCH2CH3 4,281a1', 2'7.5 H5'4.8
7 1 m Ls9.81
1 s H@(M) Colorless amorphous solid (reprecipitated from dichloromethane-n-hexane) U
ii) Elemental analysis value (as C33H56N209) c(J H@N(@ Calculated value 63.44 9.03 4.48 Experimental value 63,21 8.75 4.50 (1■) [α
] Amase 33° (c O,7, CHCl3s) Example 3 23-thioxy-23-iodo mycaminosyl silonolide 150 mg of diethyl acetal was dissolved in 3-sided anhydrous acetonitrile, and n-butylamine 70rrI
After reacting at 80C for 12 hours, the mixture was concentrated to dryness under reduced pressure. Dissolve the residue in 7.5 ml of chloroform +
Wash once each with 2.5 mt of saturated aqueous sodium bicarbonate solution and saturated aqueous solution of sulfuric acid.

After drying over anhydrous sodium sulfate, it was concentrated to dryness under reduced pressure.

120 mg of the residue was dissolved in 2.4 mt of acetonitrile.

4.9mt 0. An aqueous IN hydrochloric acid solution was added, and the mixture was reacted for 60 minutes to remove diethyl acetalization. After the reaction is complete, add 64.5 mg of hydrogen carbonate to each reaction solution,
Extracted three times with 2.4 ml of chloroform. The chloroform layers were combined and washed twice with 2.4 mt of saturated aqueous sodium sulfate solution. The residue was dissolved in 12 g of silica gel (Kie
Chromatography was carried out on a selgel 60° 230-400 mesh column using a solvent system of chloroform-methanol-concentrated aqueous ammonia (12:1:0.1).
-deoxy-23-phytylamino mycaminosyl
Got Tyronolide.

Yield 92.6 mg (yield 86%) Physical and chemical properties (1) Nuclear magnetic resonance spectrum (CDCt3) δ (ppm
) ) I number Form J (seven) Attribution 2.54
6 s 3'-N number 2~2.8
23-NH-CH2CH2C formula % formula %) fii) Colorless amorphous solid (re-precipitated from dichloromethane-n-hexane) (iii) Elemental analysis value (C8,
Horse. N20. )C(@H(-N(width calculation value 64.39 9.26 4.29Experimental value 64,42 9.46 4.45(iv)
Cα],'-zs° (c 1.0, CHC
gs) Example 4 23-deoxy-23-iodomycaminosyl quilonolide 85.5 mg of diethyl acetal was added to 1.7 m
Inbutylamine 4 was dissolved in anhydrous acetonitrile.
0.2 mg was added, and the mixture was reacted at 80C for 24 hours, and then concentrated to dryness under reduced pressure. Dissolve the residue in 4.3 ml of chloroform.

Wash once each with 2 ml of saturated aqueous sodium bicarbonate solution and saturated aqueous sodium sulfate solution, and rinse with anhydrous sulfuric acid) IJ
After drying with aluminum, the mixture was concentrated to dryness under reduced pressure. The residue was dissolved in 1.7 ml acetonitrile and 3.3 ml 0. An aqueous IN hydrochloric acid solution was added, and the mixture was reacted for 60 minutes to remove diethyl acetalization. After the reaction was completed, 28 mg of sodium hydrogen carbonate was added to each reaction solution, and the mixture was extracted three times with 1.5 mx of chloroform. Combine the chloroform layers.

Wash twice with a 1.5 mZ saturated sodium sulfate solution.

After drying with anhydrous sulfuric acid (IJ), it was concentrated to dryness under reduced pressure.

The residue was purified by silicage/l/(Kieselge) of ILg.
l 60.230=400 mesh) On the column, solvent system chloroform-methanol-concentrated aqueous ammonia (12:
1:0.1) to obtain 23-deoxy-23-inbutylamino mycaminonerutylonolide.

Yield 58.8 reports (yield 82%) Physical and chemical properties (1) Nuclear magnetic resonance spectrum (CDct3.) δ (pp
m) H number form J (Hz) Attribution 2.5
5 6 s 3'-NMet4.24
1 d,',2' 7.5 H,'4
．． 85 1 m H,.

9.82 1 s N2゜(iil
Colorless amorphous solid, (re-precipitated from dichloromethane-n-hexane) (Song Elemental analysis value (C35H6ON209 and shite)
C (%> H (%) N (%) Calculated value 64,39 9,26 4.29 Experimental value
64.21 9,09 4.52 Example 5 23-thioxy-23-iodomycaminosyl silonolide 170.9 mg of diethyl acetal was added to 3.4 m
4.98M dimethylamine acetonitrile solution was dissolved in 0.440% of anhydrous acetonitrile. mx plus 8
The reaction was carried out at 0C for 300 minutes. Then, 0.440 ml of 4.98M dimethylamine acetonitrile solution was added again, and the reaction was continued for an additional 300 minutes.

Concentrate the reaction solution under reduced pressure to remove acetonitrile.

Chloroform was added and concentrated again. The residue was dissolved in 8 ml of chloroform, washed once with 2 ml of saturated aqueous sodium bicarbonate solution and twice with 2 ml of saturated aqueous sulfuric acid solution, and then concentrated under reduced pressure.

After adding benzene to the residue, it was concentrated, and benzene-n-hexane was added and allowed to stand to obtain crystals of 23-deoxy-23-dimethylaminominocyltylonolide diethyl acetal.

- Yield: 149.7 mg (yield: 98%) 41.9 mg of the obtained crystals were recrystallized from dichloromethane-n-hexane.

Yield 36.1 mg (Recrystallization rate 86%) Physical and chemical properties (1) Nuclear magnetic resonance spectrum (CDce3) δ (ppm
) H number form J (Hz) attribution' 2.22 6
s23-NMet2.55 6
s3'-NMez4.33
1 'd1:2' 7.5 H, 〆4.53
~4.93 2 mX2 1(15,H2O(
11) Frism crystal (recrystallized from dichloromethane-n-hexane) (Elemental analysis value (C37H66N2010 ” CH
2C-e2 salt)C(%nH(%)
N (%) Calculated value 60,75 9,11 3
．． 78 Experimental value 61.09 9.09' 3.
586ψ [α] 2: +36° (c 1.
0, CHCe3) (ψ melting point 142
~144C Example 6 88.4 mg of 23-deoxy-23-dimethylamino mycaminosyl tylonolide diethyl acetal was dissolved in 1.8 ml of acetonitrile, 4.80 mx of 0.1N aqueous hydrochloric acid solution was added, and the mixture was reacted for 75 minutes.

The reaction solution was neutralized by adding 44 mg of hydrogen carbonate and then 1 ml of a saturated aqueous sodium hydrogen carbonate solution.

Extracted three times with 2 ml of chloroform. Combine the chloroform layers and dilute with 2 ml of saturated sulfuric acid).
The mixture was washed twice, dried over anhydrous sulfuric acid and concentrated under reduced pressure.

The residue was dissolved in 9 g of silica gel (Kieselgel 6
0°230-400 mesh) A column packed with chloroform-methanol-concentrated aqueous ammonia (30:1:0.1) was charged with the same solvent, and the solvent system chloroform-methanol-concentrated aqueous ammonia (15:1:0) was charged. .1) to obtain 23-deoxy-23=dimethylamino mycaminosyltylonolide.

Yield 67.9 mg (yield 86%) Physical and chemical properties (1) Nuclear magnetic resonance spectrum (CDce3) δ (ppm
) H number form JCHz) Attribution 2.22
6
23-NMez2.54 6
3'-NMe24.28 1 d+'2'7.5
H+〆9.80 1
H20 (111 Colorless amorphous solid (re-precipitated from acetone-n-hexane) +*rp Elemental analysis value (as C33H56N20o) C (%) H (%) N (%) Calculated value 6
3,44 9,03 4.48 Experimental value 6'3,7
0 9,02 4.251ψ [α] Zeng +18
° (cl, 0.cHω3) Example 7 152.1 mg of 23-thioxy-23-iodomycaminosyltylonolide diethyl acetal was dissolved in 3 mg of anhydrous acetonitrile, and 0.2 mg of diethylamine
was added and reacted at 80°C for 6 hours. The reaction solution was concentrated under reduced pressure to remove acetonitrile, chloroform was added, and the mixture was concentrated again.

Dissolve the residue in 10 ml of chloroform and add 2 ml
Wash twice with a saturated aqueous solution of sodium bicarbonate.

The mixture was dried over anhydrous sulfuric acid and concentrated under reduced pressure. The residue was mixed with 15 g of silica gel (Kieselgel 60.
230-4mm, 7mm) A column packed with chloroform-methanol and concentrated ammonia water (30:1:0.1) was stirred with the same solvent, and the solvent system chloroform-methanol-concentrated ammonia water (15:1) was stirred. :0.1) f chromatography was performed to obtain 23-deoxy-23-noethylamino 1 icaminosyl tylonolidene ethyl acetal.

Yield 129.7 mg (yield 92%) Physical and chemical properties (1) Nuclear magnetic resonance spectrum (CD (IA,) δ (pp
m) H number form J (Hz) Attribution ~ 2.4
23-N(CH2CH3)2
2.55 6 g'3'-N
Me24.36 1 d, '2' 7.5
H,'4.58-4.92 2 m
2 H+a, H2O (t++ prismatic crystal (from dichloromethane-n-hexane).

8 Shaoxing] Song 1 Elemental analysis value (as C3QH?0N2010)
C (%) H (%) N (%) Calculated value 64,43 9.71. 3.83 Experimental value 64.14 9,63 3.72qψ [α)
','' +40° (c 1.0. CHCl3s
,)M Melting point 170-171℃Example 8 23-Deoxy-23-dimethylamino mycaminosyl tylonolide diethylacetal 36.1m
Dissolve g in 0.722 mg of acetonitrile.

0.0, IN hydrochloric acid aqueous solution was added and reacted for 90 minutes.

The reaction solution was neutralized by adding 17.8 mg of hydrogen carbonate and 0.5 mg of a saturated aqueous sodium hydrogen carbonate solution.
Extracted three times with 2 mg of chloroform. Combine the chloroform layers and dilute with 2 mg of saturated sulfuric acid).
Wash twice, dry with anhydrous sulfuric acid, and concentrate under reduced pressure. For the residue, 5.5 g of silica gel (Kiese
lgel 60°230-400 mesh) Chloroform-methanol-concentrated ammonia water (30:1:0.1
) and charged with the same solvent.The solvent system was chloroform-methanol-concentrated aqueous ammonia (15:1:0.
Chromatography was performed in step 1) to obtain 23-deoxy-23-diethylamino mycaminosyl quilonolide.

Yield 31.7 mg (yield 98%) Physical and chemical properties (1) Nuclear magnetic resonance spectrum (CDCl2) δ (
ppm) H number form J (Hz) Attribution ~2.4
7 23-N(CH2CH3)
22.55 6 s 3'-NMe
24.30 1 d" 7.5 H,'
1.2 4.78 1 m Hl.

9.80 1 s H2゜(11
) Colorless amorphous solid (reprecipitated from acetone-n-hexane) GiD elemental analysis value (C35H60N209
) to C) H (to) N (5) Calculated value 64,39 9,26 4.29 Experimental value
64.54 9,11 4.06 (V) [α] +2
2° (c 1.0. CHCt3)23-deoxy-
200 mg of 23-iodo mycaminosylsilonolide diethyl acetal was dissolved in 4 ml of anhydrous acetonitrile, 0.175 ml of di-n-propylamine was added, and the mixture was reacted at 80°C overnight. The reaction solution was concentrated under reduced pressure to remove acetonitrile, chloroform was added, and the mixture was concentrated under reduced pressure again. The residue was dissolved in 1 (LmZ) chloroform, washed once with 2 mZ saturated aqueous sodium bicarbonate solution, and twice with 2 mZ saturated aqueous sulfuric acid solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. . Next(
The residue was azeotroped three times with toluene and 20 g of silica gel (Kieselgel 60.230-400
A column packed with chloroform-methanol (50:1) was charged with the same solvent, and chromatography was performed using the solvent system chloroform-methanol (61) to obtain a crude product.

Yield: 160.5 mg (yield: 80%) 110 mg of this crude product was mixed with Jig's silica gel (Kie
Chromatography was performed on a sel-gel 60.230-400 mesh column using a solvent system of chloroform-methanol-concentrated aqueous ammonia (15:1:0.1).
3-deoxy-23-dipropylamino mycaminosyl tylonolide diethylacetal was obtained.

Yield 76.7 mg (Yield approx. 82%) Physical and chemical properties ([) Nuclear magnetic resonance spectrum (CDCl2) δ (
ppm) H number form J (ratio) attribution ~1.5
3 ~ 4 m 23-N(CH2CH
2CH3) 2.37 ~ 4 m,
23-N(CH,CH2CH3)2.53 6
s 3'-N Me 24.37 1
d, l, 2/7.5 H,' (11)
Prism crystal (recrystallized from acetone-n-hexane) 0
i+) Elemental analysis value (as C41H74N2010) C (%) I N (%) Calculated value 65,22 9,88 3.71 Experimental value
64,98 9,75 3.632 [α] +50° (c 1.0. CHCL,)
~) Melting point 158-161°C Example 10 23-deoxy-23-dipropylamino mycaminosyl tylonolide diethylacetal 51.0m
Dissolve g in 1.0 ml of acetonitrile.

2.0'3 ml of 0.0, IN hydrochloric acid aqueous solution was added and reacted for 60 minutes.

The reaction solution was neutralized by adding 22.7 mg of sodium hydrogen carbonate and 1 ml of saturated aqueous sodium hydrogen carbonate solution, and extracted three times with chloroform. Combine the chloroform layers.

The mixture was washed twice with a saturated aqueous solution of sulfuric acid, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Remove the residue with silica gel (
Kieselgel 60.230-400 mesh)
on the column.

Solvent system Chloroform-methanol-concentrated ammonia water (1
5:1:0.1) to obtain 23-deoxy-23-dipropylamino mycaminosyl tylonolide.

Yield: 32.9 mg (yield: 72%) Physical and chemical properties (1) Nuclear magnetic resonance spectrum (CDCL, )δ(
ppm) H number form J (7) Attribution ~ 1.5
7 23-N(α2qsu■,)2
．． 33 ~4. m, 23-N(c)
! , CH2C1 (3) 2.54 6 8
3'-NMe24.28 1 d+'2'
7.5) It'4.77 1 m
H+s9.80 1 L
N20GiD elemental analysis value (03□H6
As 4N20Q) C (To) H (5) N (%
) Calculated value 65.27 9.47 4.11 Experimental value
65.58 9,52 3.97(iv) −
α〕+31° ((! 1.0. CHCLs')
Example 11 120.7 mg of 23-deoxy-23-iodo mycaminosyl tylonolide diethyl acetal was dissolved in 2.4 ml of anhydrous acetonitrile, 0.132 ml of di-n-butylamine was added, and the mixture was reacted at 80° C. for 20 hours.

Concentrate the reaction solution under reduced pressure to remove acetonitrile.

Chloroform was added and the mixture was concentrated again under reduced pressure. 10 residue
IJ
The mixture was washed twice with an aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in 2.4 ml of acetonitrile and 6.1 mt of 0. Add IN aqueous hydrochloric acid solution to 90
Allowed to react for minutes. Sodium hydrogen carbonate in the reaction solution 64.9
mg and 0.3 ml of a saturated aqueous sodium bicarbonate solution were added to neutralize the mixture, and the mixture was extracted three times with 2 mj of chloroform.

Combine the chloroform layers and add 2 mt of saturated sulfuric acid) IJ
The mixture was washed twice with an aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. residue.

12g of silica gel (Kieselgel 60.23
A column packed with chloroform-methanol-concentrated aqueous ammonia (30:1:0.1) was charged with the same solvent, and the solvent system chloroform-methanol-concentrated aqueous ammonia (15:1:0.1) ) to perform chromatography.

23-deoxy-23-dibutylamino mycaminosyl tyloride was obtained.

Yield 74.7 mg (yield 68.0%) Physical and chemical properties (1) Nuclear magnetic resonance spectrum (CDCL3) δ (
ppm) H number form J (7) Attribution ~2.3
5-4 m 23-N (al!2CH
2CH2C) Is) 22.54 6 s
3'-e24.32 1 dl,,i
7.5 H,'4.76 1 m
N159.80 1 s N
20(11) Colorless amorphous solid (reprecipitated from acetone-n-hexane) GiD elemental analysis value (Cse H
as N20o) C (a) H (to) N (
5) Calculated value 66.07 9.67 3°95 experimental value
65,89 9,38 3.832 (■) [α] +28° (c 1.0. CHCl3
) Example 12 23-deoxy-23-iodo mycaminosyl quilonolide diethylacetal 94GTR9 2.4
mt of anhydrous acetonitrile, added with 0.105 mg of diisobutylamine, reacted at 80° C. for 48 hours, and then concentrated under reduced pressure. The residue was dissolved in 10 ml of chloroform, washed once with 2 ml of saturated aqueous sodium bicarbonate solution and twice with 2 mg of saturated aqueous sodium sulfate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.

The obtained residue (ca, '88 mg) was transferred to 1.75 m
t of acetonitrile and 3.36 ml of 0.t. lN
Aqueous hydrochloric acid solution was added and the mixture was reacted for 60 minutes.

The reaction solution was neutralized by adding 39.5 mg of hydrogen carbonate and 0.5 mg of a saturated aqueous sodium hydrogen carbonate solution.

Extracted three times with 2 mt chloroform. The chloroform layers were combined, washed twice with 2 mg of saturated aqueous sodium sulfate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in 9 g of silica gel (Kieselgel 60
, 230-400 mesh) was charged with the same solvent into a column packed with chloroform-methanol-concentrated aqueous ammonia (30:1:0.1).

Solvent system chloroform-methanol-concentrated ammonia water C1
5:1:0.1).

23-deoxy-23-diisobutylaminomycaminosyl tylonolide was obtained.

Yield: 63.2 mg (yield: 73.6%) Physical and chemical properties.

(1) Nuclear magnetic resonance spectrum (CDCl2) δ (ppm
) H number form J (Hz) Attribution ~2.0
4 ~ 4 m 23-N(CH2CH
(CH,)2)2.53 6 3' N
Me24.30 1 d+', 2' 7.5
H+'4.73 1 m H+
s9.79 1 s -H2O(11)
Colorless amorphous solid (reprecipitated from acetone-n-hexane) (ili) Elemental analysis value (as CxHasN20o) Calculated value 66.07 9.67 3.95 Experimental value 65.98.9 ,52 3.800v) [α]
2 old 5+49° (c 1.0. CHCl5) Example 13 (a) 23,4'-dideoxy-23-iodo mycaminosyl quilonolide diethyl acetal 49,
Dissolve Omg in 0.98 mt of anhydrous acetonitrile.

Approximately 0.1 mg of 5M dimethylamine-acetonitrile solution
was added and allowed to react for 30 minutes at 80°C under a tightly closed cap. Next, an additional 0.1 mt of the dimethylamine-acetonyl IJ filtrate was added to the reaction solution, and the mixture was reacted for 30 minutes and then concentrated. After dissolving the residue in 2.5n+t of chloroform, it was washed once each with 1rr+t of a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium sulfate solution, and then dissolved in anhydrous sulfuric acid.
After drying with IJum, it was concentrated under reduced pressure.

(o) Dissolve the residue in 0.98 mt acetonitrile.

Add 1.9 mg of O, IN hydrochloric acid solution and heat at 20"C for 6 hours.
The reaction was allowed to proceed for 0 minutes. 22 mg of sodium hydrogen carbonate was added to the reaction solution, and the mixture was extracted three times with 1 mg of chloroform.

Combine the chloroform layers and add 1 mg of saturated sulfuric acid) IJ
The mixture was washed once with an aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in 5 g of silica gel (Kiese
lgel 60.230-400 mesh) on the column,
Solvent system Chloroform-methanol-concentrated ammonia water (1
Chromatography was performed at 8:1:0.1), 23.4
'-dideoxy-23-dimethylamino mycaminosyl tylonolide was obtained.

Yield 31.0 mg (yield 80%) Physical and chemical properties (1) Nuclear magnetic resonance spectrum (CDC13) δ (p
pm) H number form J (Hz) Attribution 2
．． 22 6 s 23-NMe
22.31 6 s 3'-NM
e24.23 1 d”,” 7.5
L'4.78 1 m
H+s9.83 1 s
H2゜(11) Colorless amorphous solid (re-precipitated from acetone-n-hexane) fiii)
Elemental analysis value (as C31H5°No) C (martyrdom)
H open N (g) Calculated value 65,10 9,27 4.60 Experimental value 66.21 9.16 4.370V) [α:
l'D'+23° (c 1.0. CHCl3) Sil tylonolide diethyl acetal 51, Omg was dissolved in 1.0 mg of anhydrous acetonitrile, 24.3 mg of diethylamine was added, and the mixture was reacted for 3 hours at 80° C. Next, 24. diethylamine was added to the reaction solution.
3 mg was added, reacted for 3 hours, and then concentrated. The residue was dissolved in 2.5 mg of chloroform, washed once each with 1 mt of a saturated aqueous solution of hydrogen carbonate and a saturated aqueous solution of sodium sulfate, dried over anhydrous sulfuric acid, and concentrated under reduced pressure.

(b) Dissolve the residue in 1.0 mg of acetonitrile.

0.20 mt. Add IN aqueous hydrochloric acid solution and heat at 20"C for 6
The reaction was allowed to proceed for 0 minutes. Add sodium hydrogen carbonate to the reaction solution22.
4 mg was added and extracted three times with 1 ml of chloroform. The chloroform layers were combined, washed once with 1 mg of saturated aqueous sodium sulfate solution, and then concentrated under reduced pressure.

The residue was dissolved in 5 g of silica gel (Kieselgel 60
．． 230-400 mesh) column, solvent system chloroform-methanol-concentrated aqueous ammonia (20:1:0
．． Chromatography was performed in step 1) to obtain 23.4'-diteochine-23-diethylamino mycaminosyl quilonolide.

Yield 25.7 mg (yield 61%) Physical and chemical properties (1) Nuclear magnetic resonance spectrum (CDC4) δ (pp
m) H number form J (Hz) Attribution 2.31
6 s 3'-NMe 2~
2.53 ~4 23-N(CH2
CH3) 24.25 1 d+'2'7.5
H+'4.78 1 m
H1a9.83 1 s
H2゜(11) Colorless amorphous solid (reprecipitated from acetone-n-hexane) (iji) Elemental analysis value (C3, as N2O3) H<%I N
Open calculation value 66°01 9.50 4.40 Experimental value 65.71 9,44 4.320v) [α)
V +28° (c 1.0. CHCl5) Example 15 23.4'-dideoxy-23-iodo mycaminosyl tylonolide diethyl acetal 98.0 m
Dissolve g in 2.0 mg of anhydrous acetonitrile.

82.6 mg of di-n-butylamine was added, and the mixture was reacted at 80°C for 200 hours, and then concentrated under reduced pressure. The residue was dissolved in 5 mg of chloroform and then 2 mg of saturated sodium bicarbonate 1
The mixture was washed once each with a 1 um aqueous solution and a saturated aqueous sodium sulfate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in 2 mg of acetonitrile and 2.8 mg of 0. IN hydrochloric acid water was added and the mixture was reacted for 60 minutes. After the reaction was completed, 44 mg of sodium bicarbonate was added to the reaction solution, and 2
Extracted with 3 mg of chloroform. The chloroform layers were combined, washed twice with 2 mg of saturated aqueous sodium sulfate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.

Next, 10 g of silica gel (Kieselgel 60.
230 to 400 mesh) column, solvent system chloroform-methanol-concentrated aqueous ammonia (20:1:0.
1) to obtain 23.4'-dideoxy-23-dibutylamino mycaminosyl tylonolide.

Yield 74.4 mg (yield 84%) Physical and chemical properties (1) Nuclear magnetic resonance spectrum ('CDC1,) δ (
ppm) H number Form J (Hz) Attribution 2.55 6 s 3'-
NMet~2.3 ~4 m 23
-N(CH2CH2CH2CH3)24.26 1
d+', x' 7.5 H+'
4.77 1 m H+
s9.83 1 3820 (11) Colorless amorphous solid (re-precipitated from acetone-n-hexane) +1ii) Elemental analysis value (C5oHea
As NtOa) C (to)) H open N open calculated value 67.60 9,89 4.04 experimental value 67.32 9,71 4.01 glue [α]
Amase 37° (c 1.0.CHC4) 23.4'-dideoxy-23-iodo mycaminosyl tylonolide 118 mg of diethyl acetal was dissolved in 2 A mt of anhydrous acetonitrile, and diisobutylamine 99.
After adding 1 mg of the mixture and reacting at 80° C. for 48 hours, the mixture was concentrated to dryness under reduced pressure. The residue was dissolved in 6 mZ of chloroform, washed with 2 ml of saturated hydrogen carbonate, washed once each with an aqueous IJ solution and a saturated aqueous sodium sulfate solution, dried over anhydrous sodium sulfate, and then concentrated to dryness under reduced pressure. 2.4 m of residue
t of acetonitrile, 3.4 mt of 0, IN aqueous hydrochloric acid solution was added thereto, and the mixture was reacted for 60 minutes to perform de-diethylacetalization. After the reaction was completed, 53 mg of sodium urea carbonate was added to the reaction solution, and 2.4 mt of chloroform was added to the mixture.
Extracted twice. Combine the chloroform layers, 2.4mt
The mixture was washed twice with a saturated aqueous solution of sodium sulfate, dried over anhydrous sulfuric acid, and concentrated to dryness under reduced pressure. 1 residue
20g of silica gel (Kieselge160, 230
23.4'-dideoxy-23
-Ciinobutylamino Myrikiminosyltylonolide was obtained.

Yield 75.0 mg (Yield 71%) Physical and chemical properties fi) Nuclear magnetic resonance spectra (CDCAs) δ (
ppm) H number form J (Hz) Attribution 2.32
6s3'-NMe2~2
．． 04 ~4 23-(CH2CH(
CHs,)t)t4.24 1 d,',,'
7.5 H, ・4.78 1 m
Has9.83 1s
H2゜(11) Colorless amorphous solid (
(Reprecipitation from acetone-n-hexane) (IN) Elemental analysis value (as Cse H68N206)
C(arrogant H(@N(%9 Calculated value 67.60 98.9 4.04 Experimental value 67
−38 9.82 4.16 ring ψ [α): +55°(
c 1.0, CHCl3) Example 17 23-deoxy-23-iodo mycaminosyl silonolide 199.9 mg of diethyl acetal was added to 4 mZ
The mixture was dissolved in anhydrous acetonitrile, 0.13 min of piperidine was added, and the mixture was reacted for 90 minutes in SO'C.

The reaction solution was concentrated under reduced pressure to remove acetonitrile, a small amount of chloroform was added, and the mixture was concentrated again under reduced pressure. 10 residue
The mixture was dissolved in chloroform (2 mb), washed once with a 2 mb aqueous solution of IJ and twice with a 2 mb aqueous saturated sodium sulfate solution, dried over anhydrous sulfuric acid, and concentrated under reduced pressure. To remove piperidine, the mixture was azeotroped several times with toluene and concentrated to dryness under reduced pressure. The residue was mixed with chloroform-methanol-concentrated aqueous ammonia (30:1:0.1).
20g of silica gel (Kieselgel) filled with
60.230-400 mesh) column was charged with the same solvent, and chromatography was performed using the solvent system chloroform-methanol-concentrated aqueous ammonia (15:1:0.1).
23-deoxy-23-piperidino mycaminosyltylonolide diethyl acetal was obtained.

Yield: 179.5 mg (Yield: 95 cm) 65.1 rrIg of the obtained target product was recrystallized from ethyl acetate-n-hexane.

Yield: 53.8 mg (Recrystallization rate: 82.6 cm) Physical and chemical properties (1) Nuclear magnetic resonance spectrum ('CDCl,)2.
55 6s 3”NMe
2°4.35 1 d,',2' 7.
5 H,'4.53~4.97 2
mX2 HI3. H2O (11)
Prism crystal (recrystallized from ethyl acetate-〇-hexane)
(Surface Elemental analysis value (as C40H7oN2010)C
A @ H (%) N (tIj calculated value 65
,01 9.55 3.79 Experimental value 65,12
9,33 3.56Gψ [α] +48° (c
1.0, CHCl3) (V) Melting point 166-168
°C Example 18 23-dixise 3-piperidino mycaminocil
Tyronolide diethylacetal 91.9mg I
J34 mt, dissolved in acetonitrile of 3.5
A 0.1N aqueous solution of mZ in hydrochloric acid was added and reacted for 60 minutes.

The reaction solution was neutralized by adding 41.8 mg of sodium hydrogen carbonate and 1 mt of a saturated aqueous sodium hydrogen carbonate solution.

Extracted 3 times with 1 ml of chloroform. Combine the chloroform layers and add 2 ml of saturated aqueous sodium sulfate solution.
The mixture was washed twice, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure.

The residue was dissolved in chloroform-methanol-concentrated ammonia water (
30:1:0.1) filled silica gel (Kiese
Charge the column (lgel 60.230 400 mesh) with the same solvent, and change the solvent system chloroform-methanol-
Chromatography was performed using concentrated aqueous ammonia (15:1:0.1) to obtain 23-deoxy-23-piperidino mycaminosyl tylonolide.

Yield 76.1 mg (yield 92%) Physical and chemical properties (1) Nuclear magnetic resonance spectrum (CDCl2) δ (p
pm) H number form J (Hz) Attribution 2.54
6s 3-NMe
24.30 1 d, '2' 75
H,・, 4.78 1
m H, 59,801, H2゜ (11) Colorless amorphous fixation (reprecipitation from acetone-n-hexane) (Surface Elemental analysis value (as C36H6ON20.)C
(僑H(chi)N(彌Calculated value 65,03 9.10 4.21Experimental value
64,80 8,99 3.9811y) ('
tJ, + 28° (c 1.0. CHCl3) Example 19 23-deoxy-23-iodo mycaminosyltylonolide 60.0 mg of diethyl acetal in 1.2 m
t was dissolved in anhydrous acetonitrile, 48.4 mg of nonamethyleneimine was added thereto, and the mixture was reacted with SO'C for 5 hours, and then concentrated to dryness under reduced pressure. The residue was dissolved in 3 mt of chloroform, washed once each with 1 mt of a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium sulfate solution, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. 1.2 residue
(mt acetonyl) dissolved in IJ.

1.9 ml of 0. An aqueous IN hydrochloric acid solution was added, and the mixture was reacted for 60 minutes to remove diethyl acetalization. After the reaction is complete.

Add 32 mg of sodium bicarbonate; 1. '2r
Extracted with m chloroform three times. The chloroform layers were combined and washed twice with an aqueous solution of 1.2+nZ saturated sulfuric acid.

After drying with anhydrous sulfuric acid (IJ), it was concentrated to dryness under reduced pressure.

The residue was dissolved in 6 g of silica gel (Kieselgel 60
, 230-400 MSO) column, solvent system chloroform-methanol-concentrated aqueous ammonia (15:1:0.1
) to obtain 23-deoxy-23-nonamethyleneimino mycaminosyl tylonolide.

Yield: 50.3 mg (yield: 91) Physical and chemical properties (1) Nuclear magnetic resonance spectrum (CDC13) δ (p
pm) H number HJ (Hz) Attribution 7 to \ ~2.5 4 -\ (9 system.

2゜55 6 s 3' -N
Me24.28 1 d+', z' 7.
5 H+'4.78 1 m
H, 59,801s H
z.

(11) Colorless amorphous solid (reprecipitated from acetone-n-hexane) (Surface Elemental analysis value (as C40H68N20Q) C (
Arrogance H (4N (chi) Calculated value 66.64 9.51 3.89 Experimental value
66.82 9,63 8.61QJ (α)
, + 22° (c 1.0. CHC7J3) Example 20 23-deoxy-23-iodo Mycaminone Rutylonolide Diethylacetal 90. Omg 1.8
ml of anhydrous acetonitrile, 97.2 mg of undecamethyleneimine was added thereto, the mixture was reacted at 80C for 10 hours, and then concentrated to dryness under reduced pressure. The residue was dissolved in 4.5 ml of chloroform, washed once each with 1.5 ml of a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium sulfate solution, dried over anhydrous sulfuric acid, and concentrated to dryness under reduced pressure.

8. Dissolve the residue in 1.8 ml of acetonitrile.
1mt of 0. An IN aqueous hydrochloric acid solution was added and the mixture was reacted for 60 minutes to remove diethyl acetalization. After the reaction is completed, 7
7 mg of sodium bicarbonate was added and extracted three times with 3.6 mt of chloroform. Combine the chloroform layers.

Wash twice with 3.6 ml of saturated aqueous sodium sulfate solution.

After drying over anhydrous sodium sulfate, it was concentrated to dryness under reduced pressure.

The residue was dissolved in 12 g of silica gel (Kieselgel 6
0.230-400 mesh) column, solvent system chloroform-methanol-concentrated aqueous ammonia (18:1:0.
Perform chromatography in step 1) to obtain 23-deoxy-23-
Undecamethylene imino mycaminosyl tylonolide was obtained.

Yield: 71.5■ (yield: 83) Physical and chemical properties (1) Nuclear magnetic resonance spectrum (CDCes) δ (p
pm) H number form J (Hz) Attribution ~1
．． 5 18 B -Nα: (CH,).

No 2.54 6 s 3
”-NMe2zuhaπ 〜2.5 4
CH,).

4.27 1 d+', t' 7
．． 5 H+'4.76 1 m
H.

9.81 1
H2O (11) Colorless amorphous solid (re-precipitated from acetone-n-hexane) (iii) Elemental analysis value (as C42H72N20.9) C (correspondence) H (%) N (%) Calculated value 67.35 9, 69 3.74
Experimental value 67.10 9,43 3.82 (
iv) [a] H+20° (C1,0, CHCe3
) Example 21 (I123.4'-di,deoxy-23-iodo mycaminosol tylonolide diethyl acetal 93
．． Dissolve 0 mg in 1.9 mi of anhydrous acetonitrile.

43.3 mg of pyrrolidine was added, reacted at 60°C for 80 minutes, and then concentrated under reduced pressure. The residue was dissolved in 5 ml of chloroform, washed once with 2 mt of saturated aqueous sodium bicarbonate solution and twice with 1 ml of saturated aqueous sodium sulfate solution, dried over anhydrous sulfuric acid ram, and concentrated under reduced pressure.

The mixture was azeotroped several times with toluene to remove pyrolidine.

(b) Dissolve the residue in 1.9 ml of acetonitrile.

3.4 mt of hydrochloric acid aqueous solution was added and reacted for 60 minutes.

To the reaction solution was added 41 mg of 11 um of sodium hydrogen carbonate, followed by 2 ml of a saturated aqueous solution of 11 um of sodium hydrogen carbonate, and the mixture was extracted three times with 2 m4 of chloroform. Combine the chloroform layers,'
1. The mixture was washed twice with 1 ml of saturated aqueous sodium sulfate solution, dried over anhydrous sulfuric acid, and concentrated under reduced pressure. The residue was purified with Log silica gel (Kieselgel160, 23
0 to 400 meters) on the column, solvent system chloroform-
Chromatography was performed with methanol-concentrated aqueous ammonia (18:1:0.1) to obtain 23.4'-dideoxy-23-
Pyrrolidino mycaminosyl tylonolide was obtained.

Yield 69.6 mg (yield 90%) Physical and chemical properties (1) Nuclear magnetic resonance spectrum (CDCe) 2.3
1 6 3' NMet4.
80 1 m H, 59,
831H2O (11) Elemental analysis value (as C8, H,, N2O3) C (%) H (%) N (%) Calculated value 66.42 9,33 4.34 Experimental value 66.22 9,21 4.41+m+
Ca jump + 38° (CO, 5, CHCe3) example
22 (I1 23.4'-dideoxy-23-iodomycaminosyl quilonolide diethyl acetal92.
Dissolve 3 mg in 1.9 ml of anhydrous acetonitrile,
51.4 mg of piperidine was added, and the mixture was reacted at 80C for 60 minutes, and then concentrated under reduced pressure. The residue was dissolved in 6 ml of chloroform, washed once with 2 ml of saturated aqueous hydrogen carbonate solution and twice with saturated aqueous solution of sulfuric acid, and then concentrated under reduced pressure. It was azeotroped several times with toluene to remove piperidine.

(b) The residue was dissolved in 1.9 ml of acetonitrile, 3.6 ml of F and an aqueous hydrochloric acid solution were added, and the mixture was reacted for 60 minutes.

To the reaction solution was added 40.7 mg of sodium hydrogen carbonate and then 2 ml of a saturated aqueous solution of hydrogen carbonate, and the mixture was extracted three times with 2 ml of chloroform. The chloroform layers were combined, washed twice with 2 ml of saturated aqueous sodium sulfate solution, dried over anhydrous sulfuric acid, and concentrated under reduced pressure. residue L
og silica gel (Kjeselgel 60 +23
0 to 400 meters) on the column, solvent system chloroform-
Methanol-concentrated ammonia water (18:1:0.1)
Chromatography was performed to obtain 23.4'-dideoxoto23-piperidino mycaminosyl tylonolide.

Yield 73.0 mg (yield 93%) Physical and chemical properties (1) Nuclear magnetic resonance spectrum (CDC/3) 2.3
0 6 s 3' NMe
24.25 1 d,',2' 7.5
H,'4.78 1 m
H+59.83 1
H2゜(11) Elemental analysis value (CC56H
As 6ON20) C (%) H (%) N (
%) Calculated value 66.64 9,32 4.32
Experimental value 66.93 9.05 4.20(i
iii [a 几2+36° (c 1.0, CH
Ces") (a) 23.4'-dideoxy-23-
Dissolve 62.5 mg of iodo-mycaminosyl quilonolide diethyl acetal in 1.3 ml of anhydrous acetonitrile.

Add 40.5 mg of hexamethyleneimine and keep the bottle tightly closed for 80 minutes.
After reacting with CO at C for a minute, the mixture was concentrated under reduced pressure. 'residue',
I
The mixture was washed twice with an aqueous Jumium solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure.

(b) Dissolve the residue in 1.3r+M acetonitrile, and dissolve the residue in 1.3r+M acetonitrile. 2.5 ml of IN hydrochloric acid aqueous solution was added and reacted for 60 minutes. Add 28 mg of hydrogen carbonate to the reaction solution.

Extracted three times with 1.5 ml of chloroform. The chloroform layers were combined, washed once with 1.5 ml of saturated aqueous sodium sulfate solution, dried over anhydrous sulfuric acid, and concentrated under reduced pressure. The residue was dissolved in 6 g of silica gel (Kiese
l-gel 60.230-4007) 7-) On the column, the solvent system chloroform-methanol-concentrated aqueous ammonia (
20:1:01) and 23.4'-
Diteochine-23-hexamethyleneimino mycaminosyltylonolide was obtained.

Yield: 52.4 mg (yield: 97%) (Recrystallized from acetone-n-hexane, recrystallization yield: 80
Section) Physical and chemical properties (il Nuclear magnetic resonance spectrum (CDCe3) δ(p
pm) H number form J (Hz) Attribution 1.
57 ~8 Wide S F:,,
,,West 2.31 6s
3'-NMe2~2.63
m −
Nku""? 'cH,).

C horse 4.25 1 d,',2' 7.5
H,'4.80 1 m
H.

9.83 1 H2O
(11) Colorless plate-like crystals (recrystallized from acetone-n-hexane) 1ii1 Melting point 195-19
8C (1ψ Elemental analysis value (C3?H62N20g) C (%) H (%) N (%) Calculated value 6
7.03 9.43 4.23 Experimental value 66,
91 9,21 4.03M (:/l)'
,' + 36° (C1, sail CHCe,') Example 24 (a) 23,4'-dideoxy-23-iodo mycaminosyl quilonolide diethyl acetal 7
0. Dissolve Omg in 1.4 ml of anhydrous acetonitrile, add 51.8 mg of heptamethyleneimino, and heat at 80C.
After reacting for 2.5 hours, the mixture was concentrated under reduced pressure. 3. Residue.
After dissolving in 5 ml of chloroform, add 1 ml of saturated aqueous sodium bicarbonate solution once + 1 m' of saturated sulfuric acid)
The mixture was purified twice with an aqueous solution of IJum, dried over anhydrous sulfuric acid and concentrated under reduced pressure.

(b) Dissolve the residue in 1.4 ml of acetonitrile, and add 2.8 ml of 0.5 ml of acetonitrile. IN aqueous hydrochloric acid solution was added and reacted for 60 minutes. 30 mg of hydrogen carbonate was added to the reaction solution, and the mixture was extracted three times with 1.5 ml of chloroform. The chloroform layers were combined, washed once with 1.5 ml of saturated aqueous sodium sulfate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in 7 g of silica gel (Ki
Chromatography was performed on the eselgel 60.230-400 m/n column using the solvent system chloroform-methanol-concentrated aqueous ammonia (20:1:0.1).
3.4'-dideoxy-23-peptamethyleneimino
I got mycaminocil tylonolide.

Yield 58.5 mg (yield 95%) Physical and chemical properties (1) Nuclear magnetic resonance spectrum (CDCe3) δ (p
pm) H number form J (Hz) Attribution 1
．． 52 ~lO wide B-NriCHuH,).

CH, & 2.31 6 s 3'
−NMe2~2.53 m−+lg exchange,).

4.23 1 d,',,' 7.5
H,'4.77 1 m
H.

9.83 1s H2(1(1
1) Colorless amorphous solid (re-precipitated from acetone-n-hexane) Ojil elemental analysis value (C38H64N20
8) C (%) H (coupling) N (%) Calculated value 67.42 9.53 4.14 Experimental value
67.25 9,26 4゜12fivl
[α'): + 32° (c 1.0', cHC
ex) Example 25 23,4'-dideoxy-23-iodo mycaminosyl quilonolide diethylacetal 64, Omg
was dissolved in 1.3 mt of anhydrous acetonitrile, 76.8 mg of dodecamethyleneimine was added, and the mixture was reacted at 80°C for 24 hours. After the reaction was completed, the 9 reaction solutions were concentrated to dryness under reduced pressure.

After dissolving the residue in 3.2 ml of chloroform,
mt of saturated hydrogen carbonate), washed once each with an aqueous solution of IJ and a saturated aqueous solution of sodium sulfate, and washed with anhydrous sulfuric acid) I
After drying with Jum, it was concentrated to dryness under reduced pressure. The residue was dissolved in 13 mt of acetonitrile and 45 mt of 0. An IN aqueous solution of hydrochloric acid was added, and the reaction was continued for 60 minutes at °C to remove diethyl acetate. After the reaction was completed, 28 mg of sodium hydrogen carbonate was added to the reaction solution and extracted three times with 1.5 ml of chloroform.

The chloroform layers were combined, washed twice with 5 ml of saturated aqueous sodium sulfate solution, dried over anhydrous sulfuric acid, and concentrated to dryness under reduced pressure. The residue was placed on a 7 g silica gel (Kieselgel 60.230-400 mesh) column.

Solvent system Chloroform-methanol-concentrated aqueous ammonia (2
0: l: 0.1).
23.4'-dideoxy-23-dodecamethyleneimino mycaminosyl tylonolide was obtained.

Yield: 50.2 mg (Yield: 80 cm) Physical and chemical properties (1) Nuclear magnetic resonance spectrum (CDC13) δ (p
pm) H number form J (Hz) Attribution ~ 1.3
-(co,.

CH.

2.31 6 3' --NM
e23.23 1 d,',2' 7.5
H,'4.78.1 m
H,59,831H2O (Surface Colorless amorphous solid (re-precipitated from acetone-n-hexane) (Surface Elemental analysis value (as C43H74N208) C (
@H(hate N(eIj calculated value 69,13 9,98 3.75 experimental value
68,92 9,76 3.62 (ψ [α]24
+66° (cl, o, CHCl3) Patent applicant Microbial Chemistry Research Society January 29, 1980 Haruki Gishimada, Director of the Patent Office 1 Indication of the case 1982 Patent Application No. 107485 2 Name of the invention New tie pnn derivative 3 Relationship with the case to be amended "Detailed description of the invention" column 5 of the patent applicant's specification Contents of the amendment (11 Insert the following table ■ after Table 1 on page 4 of the specification .

" Minimum effective inhibitory concentration (γ/・') [
Example 26 970111 g of 23.4'-diteoxy-23-iodo mycaminosyl typnolide diethyl acecool were dissolved in 19 ml of anhydrous 7cetonyl,
375 nTg of impulpyramine was added and heated at 78°C overnight. The reaction solution was concentrated to dryness under reduced pressure, and the resulting residue was dissolved in PP form.

After washing with a saturated aqueous sulfur bicarbonate solution and a saturated aqueous sodium sulfate solution, it was dried over anhydrous sodium chloride.

The residue obtained by distilling off the solvent was divided into 9mt of 7cells-'=
The mixture was dissolved in L-rif 1, added with 38 ml of 0.1N hydrochloric acid, and allowed to stand at room temperature for 60 minutes.

3.73 mg of sodium hydrogen carbonate was added to the reaction solution, and the mixture was extracted three times with Liproform, and the layers were combined and washed with a saturated aqueous sodium sulfate solution. Distill the solvent and +1. +Residue WOJDl-based ROROFORMUM polyol-28% ammonia, -7 water (15°l:01)
Separated and purified using a silica gel (Wako Gel C-200) column, 23.4'-dideoxy-23-impurpyramide/) mycaminosyl quilonolide 28
1 g of 0rl (yield 35%) was obtained.

Physical and chemical properties (1) Nuclear magnetic resonance spectrum (CDQ also -) -δ (pp
m) H number form J (Hz) Attribution 1.02 6 a 23-NH
-CH(CH,)21.81 1 s'
Me (22) 2.28 6
sNMe2422
1dl',' ・7.5 H+'4.8
2 1 m
H, N5.68 1 d+3. U to
H.

6, 32 1 dlo, 11 16
H+.

7.34 1 d
H.

9.72 1 m)tw
.

-(it) Elemental analysis value (C341(ss N2o
8) C (%1 H (To) N (%l Calculated value 65.57 9,39 4.50 Experimental value 65.64 9,52 4.27 (iii)
Mass spectrometry value (i) 622 (M”), 551,494,448,400
,281,174,158,98°2 4v) Infrared absorption spectrum (KBr) (cm
)2970.2940,1720,1680,159.
52g of 23.4'-thioquine-23-iodo maicami/nor type pnorite diethynoacetal 4
Dissolved in 0 ml of anhydrous 7 setonitrile, 95311
1 g of t-phthylamino was added and heated at 80°C for 1 day. The reaction solution was concentrated to dryness under reduced pressure, and the resulting residue was dissolved in a saturated aqueous sodium bicarbonate solution and saturated sulfuric acid (l) washed with an aqueous UNO solution and dried over an anhydrous sulfuric acid ram. did. The residue obtained by distilling off the solvent was dissolved in 9.3 ml of 7-cetonitrile.

39 ml of 0.2N hydrochloric acid was added, and the mixture was allowed to stand at room temperature for 60 minutes. 1 g of sodium bicarbonate was added to the reaction fiK330rl, and the mixture was extracted three times with pI:I form. The chloroform layers were combined, washed with a saturated aqueous sodium sulfate solution, and then dried over anhydrous sodium sulfate.

The residue obtained by distilling off the solvent was developed into a mixture of I:+pform-methanol-28% 7-mmonium-7 water (1s: 1:
Separate and purify with the silica gel column of 1), 2
'3.4'-dideoxy-23-(t-phthylamino)
1.12 g (yield 67%) of Mycaminocil Kuip Norai F was obtained.

Physical and chemical properties (1) Nuclear magnetism 1. sound spectrum (CDC)3) δ(p
pm) H number type J (Hz)
Attribution 1.05 9 s N
HC (CHs).

1.80 3s Me
(22) 2.24 6 s
NMet4.20 1 dbe,” 7
．． 5 n, 14.82 1
m H+s
5.64 1 d... 10
H.

6.3+ 1 d+oI+ l 6
Hl.

7.34 1 d I
(,.

9.72 1s H
20 (11) Elemental analysis value (as Css H60N20g) C (%) H (%l N (%) calculated value
66.01 9.50. 4.40 experimental value 6
5,82 9,41 4.65 (iiD Mass spectrometry value (i) 636 (M+), 551,507,462,174,
158,98.86Qv) Infrared absorption spectrum (KB
r) (cn-')2970.2940,1720
, 1680.1596 Example 28 Dissolve 1.28 g of 23.4'-endeoquine-23-iodo-inicaminosyl type diethyl 7-secure in 26 ml of anhydrous 7-cetonitrile;
730 mg of neopentylamine was added and heated at 80° C. for 6 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in chloroform, washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium sulfate solution, and then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was
Dissolve in m4 acetonitrile.

501IIt of OIN hydrochloric acid was added and allowed to stand for 60 minutes. 46.0fflg of hydrogen carbonate was added to the reaction solution, and the mixture was extracted three times with chloroform. The ctpform layers were combined, washed with saturated sulfuric acid (l) rum aqueous solution, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was developed using cyoformumeku/-no+=-28%.
23.4'-dideoxy-23
-Unopentylamino mycaminosyl Tie I: +/
Ride 48 (1 g (yield: 44%)) was obtained.

Physical and chemical properties (1) Nuclear magnetism J), (+Q spectrum (CDC))
δ (ppm)' H number form J (Hz)
Attribution 0.89 9
NH-CH2C (%\1.83 3 s
Me(22)-2,38NH-CH,
C(CH3)3. NMe24.21 1 d,
:2' 7.5 H,'4.84
1mLs 5.71 1 dls, u 1OHIs6
3θ l d+o, o 16H+.

7.31 1 d Hp9
．． 71 1 Ht.

(11) Elemental analysis value (C, as 6H62N208)C
(%l H (%) N (Complete) Calculated value 66
．． 43 9,60 4.30 Experimental value 66.15
9,32 4.54 (ti+1 Mass spectrometry value (
i) 650 (M”), 594,476.377.174,
158,100.710v) Infrared absorption spectrum (KBr) (Crn-')2970294017
2016801595 J to F Procedural amendments April 7, 1980 Commissioner of the Patent Office Haruki Shimada 1. Indication of the case 1982 Patent Application No. 107485 2. Name of the invention Novel tilecin derivative 3. Person making the amendment Related Column 5 “Detailed Description of the Invention” of the Patent Applicant’s Specification Contents of the Amendment (1) Before the name of the patent applicant at the end of page 63 of the specification, the following amendment dated January 28, 1980 is written. Following Example 28, the following Example 29 is inserted with one new line.

[Example 29 3.8 ml of 190 rQg of 23-deoxy-23-iodomycaminone rutylonolide diethyl acetal
The mixture was dissolved in anhydrous 7 setonitrile, 120 ff@ of hexamethyleneimine was added, and the mixture was heated under reflux for 60 minutes. The reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in chloroform.
Washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium sulfate solution. The chloroform layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was 1.9m
Combining Z's 7 settonitrile + 6.4 m Otsu's 0. I
After adding N-hydrochloric acid and allowing it to stand for 60 minutes, 55 tl1g of sodium hydrogen carbonate was added.

Extracted with chloroform three times. Combine the chloroform layers.

It was washed once with a saturated aqueous sodium sulfate solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. 19g of the resulting residue
Silica gel (Kjeselgel, 230-400
Purify on a mesh column with a solvent system of 28% 7-methanol-7-methanol (15:1:0.1),
128 ml of 23-thioquine-23-hexamethyleneimino mycaminone rutylonolide (yield: 78 ml) was obtained.

Physical and chemical properties (1) Nuclear magnetic resonance spectrum (CD c4) 2.53
6 3'-NM112
4.25 1 dI', 2' 7.
5 HII4.68 1
m H155,7
81d+3,1410 Ht36.25
1 d+o, o 16 Ht.

7.34 1 d 16
H.

9.72 1 d
) 120 (11) Colorless amorphous solid (iii) Infrared absorption spectrum (KBr) WN (cm
-9 Attribution 2970 CH3 2440-CH2- 1720-Coo+, -C) 10 1680; C=0 1595 - C-C-C-C- (1v) Mass spectrum (Mass) m/z: 6
78 (M”) 579. 331.174.112.
87” Procedural amendment 1987? Tsukino and Sun Commissioner of the Japan Patent Office Kazuo Wakasugi 1 Display of the case 1982 Patent Application No. 107485 2 Name of the invention New tylosin derivative 3 Relationship with the person making the amendment Case Patent applicant address Tokyo Parts Co., Ltd. Column 5 of "Detailed Description of the Invention" in the Specification No. 3-14-23, Kukami-Osaki Contents of Amendment (1) Before the name of the patent applicant at the end of page 63 of the specification, Showa [Example 30 23- Thioxy-23-iodo mycaminosyl tylonolide ethyl 7cetal 930■ acetonyl)
! 19 rnlK was dissolved, 672 ml of heptamethyleneimine was added, and the mixture was heated under reflux for 1 hour. The residue obtained by evaporating the solvent under reduced pressure was dissolved in chloroform, washed with a saturated aqueous sodium bicarbonate solution and then with a saturated aqueous sodium sulfate solution, dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The residue was dissolved in 4.6 ml of 77 tonitrile, 14 ml of 0.2N hydrochloric acid was added, and the mixture was left at room temperature for 1 hour. The reaction solution was made weakly basic by adding sodium bicarbonate, extracted with ppform, the extract was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in a solvent system of p-roform-methanol-28% aqueous ammonia (
Purified by silica gel column chromatography using ls:t:(u), 23-deoxy-
23-hebutamethyleneimy/mycaminosyl type p
1 g of Nolide 37Off (yield 45%) was obtained.

Physical and chemical properties (1) Nuclear magnetic resonance spectrum (CDC), )δ(p
pm) H number form J (Hz,) Attribution 2
．． 48 6 NMe24.
28 1 d,',,' 7.5
H,'4.76 1 m H
as5.60 1 dlg, s<10
HIs6.25 1 dlo, 11
16 Ht.

7.36 1 d H,.

9.71 1 H,.

(11) Infrared absorption spectrum (KBr) WN (
am-') Assignment 2970 -CH.

2940　　　　-CH,- 1720-Coo-, -CHO 1680>c=.

1595 -C==C-C=C-m/z:
692(M”), 661,548,502,342,
174°126.87 (IV) Elemental analysis value (C5aHaaN20o
Te) C (%) H (%) N (%) Calculated value 65.87 9,31 4.04 Experimental value 6
5,59 9.25 4.23 Procedural amendment 1981? Mr. Kazuo Wakasugi, Commissioner of the Japan Patent Office, January 2010 1 Case description 1982 Patent Application No. 107485 2 Title of invention Novel tilisin derivative 3 Relation to the case by the person making the amendment Patent applicant: I''; E: Column 5 of "Detailed Description of the Invention" of the specification, contents of amendment (: [Also, in the target compound [■], a compound in which R1 is a mono- or di-lower alkylamino group has an IRI of 7-mino group and It can also be produced by reacting the target compound (I) in which R8 is an aldehyde group with a protecting group with a halogenated lower alkyl group, and then optionally removing the protecting group of the aldehyde group.

The lower 7 liter halide is methyl iodide.

Ethyl iodide, butyl bromide, tert-butyl bromide, etc. are used.

This reaction can be carried out under heating in an organic solvent such as 7cetonitrile, acetone, dimethylformamide, etc. When 1 mole of lower alkyl halide is used, the target compound CI whose IRI is 7 mono-lower alkyl amide groups is produced. )but,
When 2 moles are used, the target compound CI) in which R8 is a di-lower fulkylami 7 group is obtained. The protective group for the aldehyde group can be removed in the same manner as in the above production method. 2) Before the name of the patent applicant at the end of page 63 of the specification, September 1, 1982? Following Example 30 of the written date and procedure amendment, the following Examples 31 and 32 are inserted in seven new lines.

[Example 31 23-7 minnow 23.4'-dideoxy mycaminosyl tylonolide diethylacetal 65ff1g
was dissolved in 1.5 mZ of anhydrous acetonitrile, 6314 g of methyl iodide was added, and the mixture was reacted at 80°C for 6 hours. The reaction solution was concentrated under reduced pressure, and the residue was extracted with 3 ml of ppform.
The mixture was washed twice with 2 ml of a saturated aqueous sodium sulfate solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. Dissolve the residue in 1.5 ml of 77 tonitrile and add 4 O, 1N hydrochloric acid.
ml and left at room temperature for 1 hour, then added 3mZ of saturated sodium bicarbonate aqueous solution and
Extracted with. The extract was dried over saturated sulfuric acid and concentrated under reduced pressure.

The residue was purified by silica gel column chromatography [eluent: 10 form-methanol-28% ammonia water (1
8:l:01)) to give 23°4'-dideoxy-2
3-dimethyl 7mino mycaminosyl quilonolide tomg was obtained.

The physical and chemical properties of this compound were consistent with those of the target product in Example 13.

Example 32 23-amino-23,4'-dideoxy mycaminosyl tylonolide Noech! Rare Acetal 661Qg
was dissolved in 6.6 m7 of anhydrous acetonitrile, and the odor (human
ert-)゛Tilt 14 inch was added and stirred at 80°C for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in chloroform 3
After extraction with 2 ml of saturated aqueous sodium bicarbonate solution, the extract was diluted twice with 2 ml of saturated aqueous sodium bicarbonate solution and then with 2 ml of saturated aqueous sodium sulfate solution.
ml of anhydrous sulfuric acid (l) ram, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography [eluent: chloroform-methanol-28% aqueous ammonia (30:1:Ol) 3, and the obtained product was dissolved in 0.5 mt of 77 tonitrile and diluted with 0.1N
1.4 rnL of hydrochloric acid was added and left at room temperature for 1 hour.

Add 1 ml of saturated aqueous sodium hydrogen carbonate solution to the reaction solution.

After extraction with 1.5 ml of chloroform, the extract was washed with 1 ml of saturated aqueous sodium sulfate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography [eluent: chloroform-methanol-28% 7-ammonium 7-aqueous (15:1:0,1)
), 23.4-dideoxy-23-Lark-
Butylamino Mycaminosyl Tyronolide 21
mg was obtained.

The physicochemical properties of this compound were consistent with the objective physicochemical properties of Example 27. "that's all

Claims (1)

[Claims] General formula [In the formula, I R is an amino group, a mono- or di-lower alkylamino group, or a formula -N>)n (wherein, n is 2 to
Represents an integer of 20. ) I R2 is a hydrogen atom or a hydroxyl group. R3 represents an aldehyde group which may have a protecting group. ] Tylosin derivative represented by.