JPH0720967B2 - 6'-Alkyl analogues of spectinomycin and process for their preparation - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to methods of synthesizing 6'-alkylspectinomycin and its analogs. Further, the present invention provides an alkyl spectinomycin-like compound having particularly excellent antibacterial activity.

Spectinomycin is a known antibiotic and was first produced by microbiological methods. See U.S. Pat. No. 3234092 to Bergy et al.

The spectinomycin analog is described by Rosenbrook Jr. et al.
Antibiotics, 28 , 953 and 960 pages (1975) and JA
ntibiotics, page 31 , 451 (1978).
Furthermore, Carney et al., J. Antibiotics, 30 , 960 pages (197
7) describes chlorodeoxy derivatives of spectinomycin. In addition, 9-epi-4 (R) -dihydrospectinomycin is described by Foley et al. In J. Org. Chem., 43 ,
22 4355-4359 (1978). However, none of the spectinomycin analogs and derivatives described in the above cited references report their biological activity.

Can.J.Chem., 51 , 53 (1973) by Lemieux:
Tri-o-to the 5-hydroxyl group of 2-deoxystreptamine (1)
Acetyl-2-deoxy-2-nitroso-α-D-glycopyranosyl chloride (2) reacts preferentially to produce α-pseudodisaturide (where CBz is carbobenzyloxy) How to do is described.

Mallams et al., J. Chem. Soc. Perkin I, page 1118 (197
6) describes a method for extending the above-mentioned Lemieux reaction to synthesize di- and tri-succharides.

Oxime removal is described by Lemieux et al. In Can. J. Chem., 51 , 19 (1973) and Mallams et al. In J. Chem. Soc. Perkin.
I, page 1097 (1976).

(1979) by Hannessian et al. Describes the chemical synthesis of spectinomycin.

White et al., Tetrahedron Letters, July, 1979 discloses the chemical synthesis of spectinomycin and its analogs. The same synthetic method appears in US Patent Application No. 150530 filed May 26, 1980, which is a continuation of the now abandoned March 3, 1979 filed No. 020172. . U.S. Patent Applications Nos. 285164 and 285165 (both filed July 20, 1981) disclose methods for making 6'-methylspectinomycin analogs and intermediates used in their synthesis.

U.S. Patent Application No. 312035, filed October 16, 1981, describes a method for demethylating spectinomycin or its analogs and a realkylation of its intermediates, and 1981 10 U.S. Patent Application No. 314261, filed March 23, describes spectinomycin analogs in which the 3'-position of spectinomycin has been converted.

In summary of the invention, copper-catalyzed Grignard addition reactions convert dienones into many types of 6'-alkylspectinomycin. Several versatile intermediates are used in that set of methods. The present invention involves converting the C-6'-position using an enone acylate.

More specifically, the invention relates to a process for the preparation of compounds of formula I which comprises using enone acylate VII as a starting material. The method is depicted and described in the reaction sequence of Scheme I.

In the above scheme, R is hydrogen or alkyl; R _{1 to} R ₉ are selected from the group consisting of hydrogen, lower alkyl, lower alkenyl and lower alkynyl; R ′ ₂ , R ′ ₃ , R ′ ₆ and R ′ ₇ Is selected from the group consisting of lower alkyl, lower alkenyl, lower alkynyl and protecting groups, said protecting group being selected from the group consisting of aralkoxycarbonyl, aralkoxycarbonyl halides and alkoxycarbonyl; provided that R ₂ and R ₃ One of them is always hydrogen
One of R ₆ and R ₇ is also always hydrogen, and R ′
'I filed One of ₃ always protecting group R' ₂ and R ₆
And R _'7 have always protecting groups one of; R ₁₀ is an acyl; A is selected from oxygen and sulfur; and B and B ₁ are identical or different connexion hydrogen, hydroxy, alkoxy, o- It is selected from the group consisting of lower alkenyl, thiol, thio-lower alkyl and thio-lower alkenyl. In step 4, R'MgX is alkyl magnesium halide (X is halogen). VI
Some intermediates between I and I and their method of preparation are described in 1979
U.S. Patent Application No. 020073 filed March 13, 2013 and No. 285164 filed July 20, 1981.

The carbon numbering shown in Compound I is used throughout the specification in its description.

The compounds prepared by the methods of this invention include the hydrated forms of the compounds of formula I. These compounds are hydrated in the 3'-position and have the formula I '.

(Wherein A, B, B ₁ , R, R ′ and R _{1 to} R ₉ are as defined above) and also include the pharmaceutically suitable salts of the compounds of formulas I and I ′.

"Lower alkyl" means methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl and its isomers.

"Lower alkenyl" means ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl and isomers thereof.

"Lower alkynyl" means ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl and its isomers.

"Acyl" means formyl, acetyl, propionyl, butyryl and pentanoyl.

"Halogenated alkoxycarbonyl" means mono-, di-,
Tri-halomethoxycarbonyl; mono-, di-, tri-
Haloethoxycarbonyl; mono-, di-, tri-halopropoxycarbonyl; mono-, di-, tri-halobutoxycarbonyl; mono-, di-tri-halopentoxycarbonyl and isomers thereof.

“Halo” means fluoro, chloro, bromo and iodo.

"Aralkoxycarbonyl" means benzyloxycarbonyl, phenylthioxycarbonyl, phenylpropoxycarbonyl, diphenyloctoxycarbonyl and its isomers and fluoroenylmethoxycarbonyl.

“Alkoxycarbonyl” means isopropyloxycarbonyl, tert-butyloxycarbonyl and tert-pentyloxycarbonyl.

Alkyl is an alkyl group having 1 to 20 carbon atoms and means both straight and branched chains.

Where one or more hydroxy or alkoxy is present in the sugar moiety, they may be the same or different, as used in this detailed description and claims. is doing.

Also described are intermediates II ', III and IV.

The dienone IV is a very versatile Michael receptor and an excellent intermediate for the transformation process.

The phrase “α-anomer” is 1 ′ below the plane of the ring system.
-Substituent is meant and the phrase "β-anomer" means the anomer having the configuration at the C-1 'position corresponding to spectinomycin.

Among the compounds produced by the method of the present invention, the β-anomer of Compound I exhibits the desired biological activity. This glycoside configuration is that found in spectinomycin shown in Scheme I above.

In step 1, enone acylate VII reacts with dimethylformamide dimethyl acetal in a solvent to produce enamine
Give rise to VI. The reaction temperature is generally in the range of 25 ° C to the reflux temperature, but 40 ° C to 80 ° C is advantageous. The reaction time is 1 to 48 hours, preferably 2 to 10 hours. Dimethylformamide dimethylacetal is used in excess. The preferred reaction time is 7 hours and the preferred solvent is dimethylformamide. Other acetals of dimethylformamide such as di-t-butyl can also be used.

The starting enone acetate and its method of preparation are described in US Patent Application No. 150530, May 16, 1980.

The enamine can be isolated from the mixture using conventional methods such as extraction, chromatography and combinations thereof.

Side chain reduction of enamine VI in step 2 is performed under standard sodium cyanoborohydride conditions to give amine V. The amine can be isolated from the reaction mixture using conventional means such as extraction, chromatography and combinations thereof.

Step 3 involves reacting amine V with an alkyl halide in the presence of a solvent to produce dienone IV. This reaction uses excess methyl iodide to produce about 0 °-
It is carried out at a temperature of about 100 ° C. for about 1 to about 30 hours. The preferred reaction temperature and time are 20 ° to 40 ° C and 1 to 20 hours.
Solvents that can be used include methylene chloride, CHCl ₃ , T
There are HF and ether. The preferred solvent is methylene chloride.

Another convenient way to carry out step 3 is to react amine V with m-chloroperbenzoic acid in a solvent to give diene IV
Is a method of producing. The reaction is carried out at a temperature of about -20 ° to about 50 ° C for about 1 to about 60 minutes. The preferred reaction temperature and time are 20 ° to 30 ° C. and 5 to 20 minutes. Solvents that can be used are ethyl acetate / skellysolve B, THF, dioxane and CH ₂ Cl ₂ . The preferred solvent is ethyl acetate / Skellysolve B.

In step 4, dienone IV reacts with the Grignard reagent in the presence of a copper catalyst to produce III. This reaction is carried out using a solvent at a temperature of about -130 ° to 0 ° C for about 1 minute to 2 hours. Preferred reaction temperature and time are -78 ° ~-
50 ° C., 1 minute to 10 minutes. Solvents that can be used include diethyl ether, 1,2-dimethylethane, THF and diisopropyl ether. The preferred solvent is THF.

In step 5, the enone III is reduced to give the protected 6'-alkylspectinomycin II. This step is a very dangerous step in the method of Scheme I for several reasons. It is very difficult to reduce the 4 ', 5' double bond without reducing the 3'-carbonyl. Palladium catalysts, ie 10% palladium on barium sulphate (ionic palladium, brown catalyst) can be used with some success but the protecting groups (especially carbobenzyloxy groups) are removed. Which would make the product separation problem more difficult. Furthermore, palladium catalysts do not work well with analogs that have highly substituted sugar side chains. Therefore, it is advantageous to use platinum oxide in the presence of solvent and base.

The second major advantage is that the protecting groups can be left behind so that the product can be chromatographically purified before using one of several protecting group elimination methods. . The reaction is carried out by dissolving enone III in a solvent, adding base and platinum oxide and contacting the mixture with hydrogen. The reduction is carried out at about 20-40 ° C for about 1-4 hours. The preferred temperature and reaction time is 20-40 ° C,
2 to 3 hours.

Another convenient way to carry out step 5 is to protect III by reacting didehydrospectinomycin III with Li-selectride (a solution of tri-sec-butyllithium borohydride). -Spectinomycin I
It is to reduce to I. This reaction is carried out by dissolving didehydrospectinomycin III in a solvent, adding a lithium solution, and then adding a base and water. The reduction is carried out at about -100 ° -10 ° C for 5-60 minutes. The preferred temperature and reaction time are -78 ° to -10 ° C and 5 to 40 minutes.
Solvents that can be used include THF, dioxane, 1,2-
There are dimethoxyethane and diethyl ether. The preferred solvent is THF.

In step 6, the compound of formula II is deprotected to remove the compound of formula I
Yields the compound of. Conditions for leaving protecting group protects the individual groups, that is, the amine of Akuchinamin ring R _'2
Or determined by the R _'3 and R' ₆ or R _'7. When the group is benzyloxycarbonyl or aralkoxycarbonyl, the protecting group elimination reaction is suspended in a solvent (eg, isopropanol, absolute ethanol, anhydrous methanol, ethyl acetate, toluene or tetrahydrofuran) to give palladium black, palladium. -
It is carried out under hydrogen at -10 psi to +200 psi with conventional catalysts such as carbon, palladium-barium sulfate or palladium-barium carbonate. It is sometimes convenient to generate hydrogen in situ from formic acid in methanol.

Alternatively, the protection MotoHanare compound R _'2 or R' ₃ and R _'6 or R' ₇ is alkoxycarbonyl or aryloxycarbonyl are carried out in the presence of a solvent in an acid such as nitromethane and methylene chloride Be done.

When R _'2 or R' ₃ and R _'6 or R' ₇ is halo alkoxycarbonyl, leaving the protecting groups is advantageously carried out in the presence of zinc.

A particularly convenient method for preparing compounds of formula VI is Scheme II
Indicated by.

Step 1 involves reacting N, N'-dibenzyloxycarbonylspectinomycin (see JACS, 85 , p. 2652, 1963) with formic acid in the presence of acetic anhydride, ethyl acetate and pyridine. This reaction is about -70 ° -10 ° C
At about 1/2 to 30 hours in the presence of a solvent. The preferred temperature range is about -40 ° to 0 ° C and the preferred reaction time is about 10-18 hours. The solvent that can be used is ethyl acetate,
There are tetrahydrofuran, methylene chloride, chloroform and 1,2-dimethylethane. The preferred solvent is ethyl acetate. Step 1 produces a compound of formula IX.

In step 2, the compound of formula IX reacts with acetic anhydride and base to give the compound of formula VIII. This reaction is carried out in the presence or absence of a solvent at about 20 ° to 90 ° C (preferably 50 ° to 70 ° C).
C.) for about 2 to 30 hours (preferably 10 to 20 hours). Solvents that can be used include ethyl acetate, tetrahydrofuran, 1,2-dimethyloxyethane and chloroform. The preferred solvent is ethyl acetate.

In step 3, compound VIII is treated with light in the presence of dibromodimethylhydantoin to give C ₃ -carbonyl in the form of the compound of formula VII. This reaction is about 10 ° -100
℃ (preferably 40 〜 80 ℃) for about 2-60 minutes (preferably
10-20 minutes). In this process, 4 ', 5'
An unsaturated bond is formed at the -position.

In step 4, the compound of formula VII reacts with dimethylformamide acetal in the presence of dimethylformamide and the reaction product reacts with methanol or water to give the compound of formula
This produces a compound of VI. This reaction is carried out at about 30 ° to 90 ° C (preferably 40 ° to 70 ° C) for about 2 to 6 hours (preferably 3 to 5 hours). Each product produced in the above steps can be isolated from the reaction mixture by conventional means.

Any method within the skill of the art can be used to isolate analogs of the compounds of formula I, and is not limited to the methods described herein. If the isolation is carried out under anhydrous conditions, compounds having a carbonyl group in the 3'-position (formula I) are obtained. When performed under aqueous conditions, compounds VII and VI are excluded (these compounds are not hydrated) to give compounds hydrated in the 3'-position (formula I ').

Crude product is Amberlite IRC-50 or C
Adsorbed on a column of weakly acidic ion exchange resin such as G-50, followed by water containing hydrochloric acid, hydrobromic acid, hydroiodic acid and sulfuric acid, methanol, ethanol, ether, tetrahydrofuran, 1,2-dimethoxy. It can be purified by eluting with a solvent such as ethane or p-dioxane.

The acid salt is a compound of formula I with a suitable acid at about pH 7.0 or below,
It can be produced advantageously by neutralization to about pH 2 to pH 3. Acids suitable for this purpose include hydrochloric acid, sulfuric acid, phosphoric acid,
There are sulfamic acids, hydrobromic acids and similar acids. The acid and base salts of the compound can be used for the same biological purposes as the parent compound.

The compounds of formula I inhibit microbial growth in various environments. For example, compounds of formula I having the β-configuration are active against Escherichia coli and reduce slime formation in the paper industry by using its antibacterial activity against E. coli to prevent, block and eradicate it. Can be used for These β-anomers are also found in the Trichomonas foetu ( Trichomonas foetu).
s), Trichomonas hominis (Trichomonas homini
s ) and Trichomonas vaginalis ( Trichomonas va
ginalis ) can be used to prolong these culture lives by releasing it from E. coli contamination. Furthermore, the β-anomer is a Bacillus subti
lis ) and can thus minimize or prevent the malodor of fish and fish-carrying bamboo baskets caused by this fungus. Β-anomers are also used to wipe work surfaces and equipment in microbiological laboratories. β-anomers are also effective against Klebsiella pneumoniae .

The compounds of formula I are also effective in treating bacterial infections such as phobia in mammals, including humans.

Compounds exhibiting good antibacterial activity are compounds of the formula I in which R'is a straight-chain, cyclic or branched alkyl group (where the longest extension of the branched or cyclic chain is 1 to 4 carbon atoms). Including). Examples of R'include ethyl, propyl, isopropyl, butyl, t-butyl and cyclohexyl. 6'-n-propylspectinomycin, 6'-n-butylspectinomycin and 6 '
-Pentylspectinomycin is a particularly potent antibacterial agent.

It is provided for administration to humans or animals in unit dosage form such as sterile parenteral solutions or suspensions, eye drops and water-in-oil emulsions containing suitable amounts of a compound of formula I of the invention.

For parenteral administration, liquid unit dosage forms are prepared using a compound of formula I and a sterile vehicle, water being preferred.
The compound, depending on the vehicle and concentration used, is either suspended or dissolved in the vehicle. To prepare solutions, the compound is dissolved in distilled water for injection and oversterilized before filling into suitable vials or ampoules and sealing. Advantageously, adjuvant agents such as local anesthetics, preservatives and buffers are dissolved in the vehicle. To increase stability, the composition is filled into vials and then frozen to remove water under vacuum.
The lyophilized powder is then sealed in a vial and an accompanying vial of distilled water for injection is prepared and reconstituted into a liquid before use. Parenteral suspensions can be prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, but it cannot be sterilized by excess. The compound is sterilized by exposure to ethylene oxide before suspension in a sterile vehicle. Advantageously, a surfactant or wetting agent is added to the composition to ensure a homogeneous distribution of the compound.

The phrase "unit dosage form" as used herein refers to physically discrete units suitable as a single pharmaceutical agent for human patients and animals, each unit being a pharmaceutical diluent, carrier or vehicle. In combination with a predetermined amount of active substance calculated to produce the desired therapeutic effect. The specification for the novel unit dosage forms of the present invention is (a) a unique substance of the active substance and the particular effect to be achieved,
And (b) directly dependent on the limitations inherent in the art of formulating such actives for use in humans and animals, which is also a feature of the present invention. Examples of suitable unit dosage forms consistent with the present invention include ampoules, vials, exhalable aerosols, multiple separations of any of the foregoing, and other dosage forms described herein. is there.

An effective amount of compound is used for treatment. The dosage of the therapeutic compound will be determined by a number of factors well known to those skilled in the art. These factors include, for example, the route of administration and its potency of the particular compound. When a composition comprising a compound of the invention is administered parenterally to a human, it is effective for bacterial infection to administer about 2-4000 mg of the compound in a single dose. More specifically, the single dose is about 5-200 mg of compound.

The following preparation of spectinomycin analogs illustrates the scope of the invention, but is not to be construed as limiting. Those skilled in the art will readily recognize not only the reaction conditions of the method of the present invention and its operating methods, but also variations from both methods of spectinomycin analogs of the novel compounds and their precursors described herein.

For example, in the Preparations and Examples set forth below, the stereoisomers corresponding to each of the named compounds are expected to be within the scope of the invention.

Production Example 1 N, N'-dibenzyloxycarbonyl-2,6-
Di-o-formyl-spectinomycin In a 5 liter flask equipped with stirrer and thermometer were placed ethyl acetate (1.33 liter) and 97% formic acid (255 ml). Acetic anhydride (618 ml) was added and cooled with dry ice / acetone to keep the temperature below -40 ° C. Pyridine (1.09 l) was added slowly so that the temperature was about -40 ° C. N, N'-dibenzyloxycarbonyl spectinomycin (100g)
Was added and stirring was continued overnight and the cooling bath was allowed to reach room temperature. The solution is ethyl acetate (1.65l)
Diluted with 0.5N hydrochloric acid (5 x 675 ml), water (2 x 675 m
l), washed with 10% aqueous sodium bicarbonate solution (2 x 675 ml) and brine (2 x 175 ml). The organic layer was dried and concentrated to give N, N'-dibenzyloxycarbonyl-2,6-di-o.
-105 g of formyl spectinomycin was obtained.

CMR (d ₆ -acetone): 201.6, 161.4, 161.0, 157.1, 1
3.6, 129.1, 128.4, 128.1, 97.1, 92.1.73.7, 71.7, 6
8.3, 67.7, 67.6, 65.9, 56.1, ppm.

Using the appropriately substituted N, N'-dibenzyloxycarbonyl spectinomycin instead of N, N'-dibenzyloxycarbonyl spectinomycin, the diisocyanates of Tables I and II were prepared in the same manner as in Preparation Example 1. The -o-formyl spectinomycins were obtained.

Production Example 2 N, N'-dibenzyloxycarbonyl-2,6-
Di-o-formyl-2'-o-acetylspectinomycin enol acetate N, N'-dibenzyloxycarbonyl-2,6-di-o-formyl spectinomycin (7.0g), acetic anhydride (15.0m
l), pyridine (30.0 ml) and dimethylaminopyridine (0.5 g) in a 250 ml flask with ethyl acetate (50 ml).
And heated to 55 ° C. overnight. The reaction mixture was diluted with ethyl acetate (500 ml) and hexane (500 ml), 0.6N
Hydrochloric acid (3 × 1), (1 × 0.5 l) then saturated sodium bicarbonate solution (2 × 500 ml) and brine (2 × 500 m)
l) washed. Dry the organics over sodium sulfate and concentrate
7.0 g of N, N'-dibenzyloxycarbonyl-2,6-di-o-formyl-2'-o-acetylspectinomycin enol acetate was obtained.

CMR (d ₆ -acetone): 168.9, 167.7, 161.4, 161.0, 15
7.1, 139.9, 137.8, 129.1, 128.4, 128.2, 128.1, 12
2.8, 94.7, 92.2, 74.1, 71.3, 69.1, 67.6, 67.2, 56.
3, 55.5, 31.4, 30.7, 21.1, 21.0, 20.7ppm.

N, N'-dicarbobenziloxycarbonyl-2,6-di-o
Using the appropriately substituted 2,6-di-o-formylspectinomycin instead of -formylspectinomycin, the enamines of Tables III and IV were obtained in the same manner as in Preparation Example 2.

Production Example 3 N, N'-dibenzyloxycarbonyl-2,6-
Di-o-formyl-2'-o-acetyl-4 ', 5'-didehydrospectinomycin N, N'-dibenzyloxycarbonyl-2,6-di-o-formyl-2'-o-acetyl Spectinomycin enol acetate (5.26g) was dissolved in carbon tetrachloride (75ml) and dibromodimethylhydantoin (1.05g) was added. The solution was refluxed under visible light as an initiator. After 20 minutes the solution was cooled and diluted with chloroform (200 ml) and water (100 ml). The phases were separated and the organic phase was washed with aqueous sodium chloride solution (60 ml). The organic phase is dried over sodium sulphate and concentrated to give N, N'-dibenzyloxycarbonyl-
There were obtained 5.65 g of 2,6-di-o-formyl-2'-o-acetyl-4 ', 5'-didehydrospectinomycin.

CMR (d ₆ -acetone): 182.4, 173.4, 170.0, 161.6, 16
1.0, 157.0, 137.6, 129.2, 128.6, 128.2.103.4, 95.
7, 93.1, 73.7, 72.1, 67.8, 66.9, 56.1, 55.7, 31.
8, 30.6, 21.0ppm.

N, N'-Dibenzyloxycarbonyl-2,6-di-o-formyl-2'-o-acetylspectinomycin Similar to Preparation Example 3 using appropriately substituted enol acetate instead of enol acetate The 4 ', 5'-didehydrospectinomycins of Tables V and VI were obtained by the method of.

Production Example 4 N, N'-dicarbobenziloxy-2'-o-
Acetyl-6 '-[(dimethylamino) methylene]-
4 ', 5'-didehydrospectinomycin N, N'-dicarbobenziloxy-2'-o-acetyl-4', 5'-didehydrospectinomycin (22.00 g, 34, in dimethylformamide (100 ml) 4 mmol) and dimethylformamide dimethyl acetal (100 ml) were dry protected and stirred at 50-55 ° C. for 7 hours. The brown solution was concentrated under vacuum and the residue was washed with silica gel (250
Chromatography was carried out using a wet-filled glass filter (g, 2 liters). The mixture is 5% acetonitrile in chloroform (2l), 7% (3l), 33% (3l), 50% (6l)
The mixed solution of was eluted for 1 1/2 hours. 1/2
l Collected each fraction. Fraction was evaluated by TLC (mixed solvent of acetonitrile: chloroform 1: 1), and combined with pure N, N'-dicarbobenziloxy-
2'-o-acetyl-6 '-[(dimethylamino) methylene] -4', 5'-didehydrospectinomycin 19.78g
And some DMF (dimethylformamide)
N, N'-dicarbobenziloxy-2'-o-acetyl-
There was obtained 3.30 g of 6 '-[(dimethylamino) methylene] -4', 5'-didehydrospectinomycin. The latter fraction was rechromatographed as above (but using 60 g of silica gel) to give pure N, N'-dicarbobenziloxy-2'-o-acetyl-6'-
2.75 g of [(dimethylamino) methylene] -4 ', 5'-didehydrospectinomycin was obtained. Total yield 22.53g
(Yield 94%).

CD (CH ₃ OH) [θ] ₃₁₁ nm-10,400 ± 1,200, [θ] _285-
2,500 ± 1,200, [θ] ₂₄₆ -1,200 ± 1,200.

IR (Mull): 3380, 1750, 1695, 1675sh, 1600, 1555, 1
500, 1385, 1350, 1280, 1240, 1195, 1185, 1145, 111
0, 1085, 1065, 1025, 1000, 960, 770, 740, 645c
m ^-1 .

PMR (CDCl ₃ ): 2.13 (3H, s), 2.82 (3H, s), 2.89 (6H, s)
Wide s), 2.91 (3H, s), 5.10 (4H, wide s), 5.16 (1
H, s), 5.97 (1H, s), 7.30δ (10H, s).

CMR (CD ₃ COCD ₃ ): 20.9, 31.2, 31.5, 30-44 wide, 36.
3, 59.6, 66.2, 67.3, 74.6, 75.4, 88.7, 94.9, 95.
0, 95.1, 95.5, 128.3, 129.1, 137.9, 138.0, 150.3,
157.2, 157.7, 163.3, 169.8, 171.2, 180.3ppm.

Mass spectrum, m / c (diTMS): 839 (M ⁺ ), 824, 797,
779, 730, 688. Calculated for peak: 839.3480; found: 839.3466.

N, N'-dicarbobenziloxy-2'-o-acetyl-
The enamines of Tables VII and VIII were obtained in a similar manner to that of Preparation 4, using the appropriately substituted enone acetate instead of 4 ', 5'-didehydrospectinomycin.

Production Example 5 N, N'-dicarbobenziloxy-2,6-di-o
-Formyl-2'-o-acetyl-6 '-[(dimethylamino) methylene] -4', 5'-didehydrospectinomycin N, N'-dibenzyloxycarbonyl-2,6-di-o- Formyl-2'-o-acetyl-4 ', 5'-didehydrospectinomycin (5.50g) was added to dimethylformamide (39.0m
l) and dimethylformamide dimethyl acetal (36.0 ml) was added. After heating at 55-60 ° C for 4 hours, methanol (36 ml) was added, and heating at 55-60 ° C was continued for 3 hours. The residue was taken up in chloroform (15 ml) and chromatographed on silica gel (200 ml) in a filter. Product eluted after residual DMF by elution with chloroform (1/2 l), 5% acetonitrile in chloroform (0.8 l), 30% acetonitrile in chloroform (150 ml) and acetonitrile (1). . The fractions were combined to produce N, N'-dicarbobenziloxy-2,6-di-o-formyl-2'-o-acetyl-6 '-[(dimethylamino) methylene] -4', 5 '.
2.71 g of didehydrospectinomycin was obtained.

CMR (d ₆ -acetone): 180.3, 171.2, 169.8, 157.0, 15
0.3, 137.9, 129.0, 128.2, 95.5, 95.2.95.1, 94.8, 8
8.7, 75.3, 67.3, 66.2, 59.9, 56.7, 41.0, 31.4, 30.
7, 21.2ppm.

N, N'-dibenzyloxycarbonyl-2,6-di-o-formyl-2'-o-acetyl 4 ', 5'-didehydrospectinomycin, appropriately substituted 4', 5 ' The enamines of Tables IX and X were obtained in the same manner as in Preparation Example 5 using -didehydrospectinomycin.

Production Example 6 N, N'-dicarbobenziloxy-2'-o-
Acetyl-6 '-(dimethylaminomethyl) -4', 5 '
-Didehydrospectinomycin N, N'-dicarbobenziloxy-2'-o-acetyl-
6 '-[(dimethylamino) methylene] -4', 5'-didehydrospectinomycin (20.00 g, 28.78 mmol) and methyl orange (5 mg) in methanol (200 m
dissolved in l). Adjust the pH to 4 with 2N methanolic HCl and add sodium cyanoborohydride to 2N methanolic HCl.
HCl was added in small portions over 20 minutes with frequent readjustments of pH. After adding a total of 2.00 g (31.83 mmol) of sodium cyanoborohydride, the solution was further stirred at room temperature until TLC (mixed solvent of methanol / chloroform 1: 9) showed no starting material. The solution was concentrated and ethyl acetate (500ml), 0.1N NaOH
(250 ml), 1.0 N NaOH (25 ml) and saturated brine (25 ml)
0 ml). The organic phase is brine (200ml + 100ml)
Washed with. The three aqueous phases were washed successively with ethyl acetate (2 x 200 ml). The organic extract was dried over sodium sulfate and concentrated to give a foamy N, N'-dicarbobenziloxy-2 '.
-O-Acetyl-6 '-(dimethylaminomethyl)-
17.93 g of 4 ', 5'-didehydrospectinomycin (yield
89%).

CD (CH ₃ OH) [θ] ₃₂₁ -12,000 ± 1,100, [θ] ₂₇₀ ± 1,
100.

UV (C ₂ H ₅ OH): 273 nm (8,800), 377 nm (shoulder) (63).

PMR (CDCl ₃ ): 2.13 (3H, s), 2.17 (6H, s), 2.46 (3H, s)
s), 3.05 (3H, s), 3.06 (3H, s), 5.05 (4H, d), 5.3
4 (1H, s), 5.89 (1H, s), 7.26 (10H, d).

CMR (CD ₃ COCD ₃ ): 20.9, 31.3, 45., 56.1, 57.1, 61.
3, 66.1, 67.3, 74.0, 75.4, 93.7, 96.0, 103.1, 128.
3, 129.1, 137.9, 157.2, 170.0, 174.9, 183.1ppm.

Production Example 6a N, N'-dicarbobenziloxy-2'-o-
Acetyl-6 '-(dimethylaminomethyl) -4', 5 '
-Didehydrospectinomycin N, N'-dicarbobenziloxy-2'-o-acetyl-
6 '-[(Dimethylamino) methylene] -4', 5'-didehydrospectinomycin (57.0 g, 78.7 mmol). Ethyl acetate (450ml) and methanol (105ml)
Were mixed. The pH was adjusted to 4 with 2N hydrochloric acid, and sodium cyanoborohydride (7.3g) was added in 5 batches over 5 minutes while adjusting the pH to 4 with 2N hydrochloric acid. Another 15 minutes after the sodium cyanoborohydride addition is complete
The pH was maintained at 4. TLC (methanol / chloroform 1: 9
Mixed solvent) showed that the starting material was consumed. Then the solution was mixed with NaOH and the phases were separated. The upper phase was drained with brine (250 ml) and Skelisulve B (150 ml) was added to break the suspension. The two aqueous phases are combined with ethyl acetate (300m
The mixture was sequentially backwashed with a mixed solvent of l) and Skelisolve B (75 ml), and the whole organic phase was dried over sodium sulfate. N, N'-Dicarbobenziloxy-over sodium sulfate
2'-o-acetyl-6 '-(dimethylaminomethylene)
A solution containing -4 ', 5'-didehydrospectinomycin was obtained.

N, N'-dicarbobenziloxy-2'-o-acetyl-
Tables VII and VIII instead of 6 '-[(dimethylamino) methylene] -4', 5'-didehydrospectinomycin
The protected spectinomycin analogs of Tables XI and XII were obtained by procedures similar to Preparations 6 and 6a using the appropriately substituted precursor enamines from.

Production Example 7 N, N'-dicarbobenziloxy-2'-o-
Acetyl-6'-methylene 4 ', 5'-didehydrospectinomycin N, N'-dicarbobenziloxy-2'-o-acetyl-
6 '-(Dimethylaminomethyl) -4', 5'-didehydrospectinomycin (17.43 g, 25.00 mmol) in methylene chloride (200 ml) and methyl iodide (18.0 ml, 41.
(04 g, 289 mmol) and stirred at room temperature for 6 hours.
After standing at 10 ° C. for a further 16 hours, the solution was concentrated, and the residue was dissolved in a mixed solvent of acetonitrile / chloroform 1: 9. The mixture was chromatographed on silica gel (300 g) using the same solvent as above (4 l) and then a mixed solvent of acetonitrile / chloroform 1: 3 (4 l). The fractions of the first pure substance eluted were combined and concentrated to give 10.03 g of N, N'-dicarbobenziloxy-2'-o-acetyl-6'-methylene-4 ', 5'-didehydrospectinomycin ( Yield 61%) was obtained.

CD (CH ₃ OH) [θ] ₃₃₄ ‐26,100 ± 2,300, [θ] ₂₄₀ -4
4,800 ± 2,300, [θ] ₂₂₄ nm-10,800 ± 2,300.

UV (C ₂ H ₅ OH) 204 shoulders (22,500), 241 (6.750) 250 shoulders (5,900), 256 shoulders (4,900), 293nm (14,650).

PMR (CDCl ₃ ): 2.13 (3H, s), 3.03 (3H, s), 3.06 (3H, s)
s), 5.05 (4H, d), 5.44 (1H, s), 5.61 (1H, q), 5.9
5 (1H, s), 6.11 (1H, s), 6.19 (1H, s), 7.29pp (10
H, s).

CMR (CD ₃ COCD ₃ ): 20.9, 31.4, 57.2, 60.1, 66.2, 67.
4, 74.1, 74.7, 75.6, 94.0, 96.1, 104.3, 125.3, 12
8.4, 129.2, 131.1, 138.0, 138.1, 157.6, 166.6, 17
0.2, 184.0ppm.

Production Example 7a N, N'-dicarbobenziloxy-2'-o-
Acetyl-6'-methylene-4 ', 5'-didehydrospectinomycin N in ethyl acetate / Skellysolve B prepared in Preparation 6a,
N'-dicarbobenziloxy-2'-o-acetyl-
M-Chloroperbenzoic acid (15 g) was added to 6 '-(dimethylaminomethyl) -4', 5'-didehydrospectinomycin. The solution was stirred for 10 minutes, then saturated sodium bicarbonate solution (300 ml) was added with mixing and the phases were separated. The organic phase was washed with brine (250 ml) then methanol was added to break the emulsion. Two aqueous fractions, ethyl acetate (250 ml) and Skellysolve B (75 ml)
It was washed successively with the mixed solvent of. The organic phases were combined, dried over sodium sulfate and concentrated to a solid. The solid was dissolved in chloroform, and the solution was dissolved in silica (1 wet-filled in a glass filter of 1) with chloroform (4 liters), 2
% Acetonitrile / chloroform (2l), 5% acetonitrile / chloroform (2l), 10% acetonitrile (4l
Chromatograph using l) and 15% acetonitrile (4 l). Fractions 10 to 14 are combined and concentrated to give 15.7 g of a mixture containing N, N'-dicarbobenziloxy-2'-o-acetyl-6'-methylene-4 ', 5'-didehydrospectinomycincin. Obtained.

N, N'-dicarbobenziloxy-2'-o-acetyl-
Using the appropriately substituted didehydrospectinomycin instead of 6 '-(dimethylaminomethyl) -4', 5'-didehydrospectinomycin, a procedure similar to that of Preparations 7 and 7a was used to prepare Table XIII and A protected spectinomycin analog of XIV was obtained.

Production Example 8 N, N'-dibenzyloxycarbonyl-2 '
-O-Acetyl-4 ', 5'-didehydro-6'-n-octylspectinomycin A dry 15 ml three-necked flask was equipped with a magnetic stir bar and serum cap. Dissolve N, N'-dicarbobenziloxy-2'-o-acetyl-6'-methylene-4 ', 5'-didehydrospectinomycin (332 mg, 0.5 mmol) in tetrahydrofuran (10 ml) Copper (25mg)
Was added. The slurry was cooled to -78 ° C under nitrogen atmosphere and then heptylmagnesium bromide (1.2 ml, 2.1 mol)
The solution was added by injection through the cap solution. TLC (C
H ₃ OH: CHCl ₃ 1: 4) showed that the starting material was converted to a slightly less polar main product. The reaction mixture was poured into a mixed solution of ethyl acetate (20 ml) and acetic acid (0.3 ml). After diluting with water (10 ml) and mixing, the organic phase was separated and washed with saturated sodium bicarbonate solution (15 ml) and saturated brine (10 ml). The aqueous extract was washed sequentially with ethyl acetate (20 ml). The organic extract was dried over sodium sulfate and concentrated to a foam. Purified N, N'-dibenzyloxycarbonyl-2'-o-acetyl-4 ', 5'-didehydro-6' chromatographed on 6.0 g of silica in a mixed solvent of acetonitrile-chloroform 1: 9. 0.32 g of -n-octyl spectinomycin was obtained.

CMR (CD ₃ COCD ₃ ): 183.1, 178.4, 170.0, 157.7, 138.
0, 124.1, 128.3, 102.5, 96.0, 93.8, 75.6, 73.4, 6
7.3, 66.1, 59.7, 57.2, 35.0, 32.4, 31.4, 30.0, 29.
8, 29.6, 26.7, 23.2, 20.4, 14.3ppm.

Mass spectrum (silylated): m / e 856 (M ⁺ ),
841, 769, 671, 600, 484, 356, 313, 284, 243, 217,
199, 171, 145, 73.

The following 6'-alkylspectinomycins were obtained in a similar manner to that of Preparation 8 using alkyl magnesium bromide appropriately substituted in place of heptyl magnesium bromide.

N, N'-dibenzyloxycarbonyl-2'-o-acetyl-4 ', 5'-didehydro-6'-ethyl-spectinomycin; CMR 183.1, 176.2, 170.0, 151.3, 137.81, 129.0, 12
8.1, 102.6, 95.9, 93.6, 75.3, 74.2, 67.3, 66.1, 6
0.0, 57.1, 36.8, 31.3, 20.8, 20.0, 13.6ppm.

N, N'-dibenzyloxycarbonyl-2'-o-acetyl-4 ', 5'-didehydro-6'-n-propylspectinomycin; CMR 183.3, 176.5, 170.1, 157.2, 138.2, 129.2, 128.
4, 102.6, 96.1, 93.8, 75.6, 74.6, 67.4, 66.2, 60.
1, 57.3, 34.8, 32.2, 28.8, 22.7, 20.9, 13.9ppm.

N, N'-dibenzyloxycarbonyl-2'-o-acetyl-4 ', 5'-didehydro-6'-n-butylspectinomycin; CMR 183.1, 176.4, 170.0, 157.9, 138.2, 129.1, 128.
7, 102.5, 96.0, 93.8, 75.6, 74.6, 67.3, 66.1, 60.
0, 57.2, 35.0, 31.7, 31.4, 26.3, 22.8, 20.9, 14.1p
pm.

N, N'-dibenzyloxycarbonyl-2'-o-acetyl-4 ', 5'-didehydro-6'-n-pentylspectinomycin; and CMR 183.1, 176.5, 170.0, 157.8, 138.4, 129.1, 128 .
3, 102.6, 96.0, 93.7, 75.6, 74.8, 67.3, 66.0, 60.
2, 57.1, 35.0, 32.0, 31.4, 29.2, 26.6, 23.0, 20.
9, 14.2ppm.

Table XV and XVI N, N'-dibenzyloxycarbonyl-
2'-o-acetyl-4 ', 5'-didehydro-6'-n-octylspectinomycin analog.

Production Example 9 N, N'-dibenzyloxycarbonyl-6 '
-Octylspectinomycin N, N'-dicarbobenzyloxy-2'-o-acetyl-
4 ', 5'-Didehydro-6'-n-octylspectinomycin (0.32g) was dissolved in 2-propanol (12.0ml) and triethylamine (0.12ml) was added. The solution was divided into four equal portions and placed in test tubes each containing 30 mg of platinum oxide. Carefully place the test tube in the pearl bottle and
Shake with psi hydrogen for 2 hours. Over the catalyst, water (0.7 ml) was added to the combined liquors. After standing for 16 hours, the solution was heated at 65 ° C. for an additional 3/4 hour, concentrated and chromatographed on silica (6 g). N, N'-dibenzyloxycarbonyl-6'-n-octylspectinomycin was added to 0.5% methanol / chloroform (200m
l) 1% (100ml), 1.5% (150ml), 2% (200ml)
And eluted with 3% (100 ml). The desired fraction was found by TLC analysis (the product produced a purple spot when heated with a DNP spray followed by a sulfuric acid spray). The product yield was 0.09 g.

CMR (CD ₃ COCD ₃ ): 201.5, 157, 138.1, 129.1, 128.3, 9
7.5, 92.3, 75.1, 74.7, 74.6.71.8, 67.2, 66.4, 65.
6, 61.1, 60.1, 57.5, 44.1, 36.1, 32.4, 31.7, 31.
4, 30.7, 30.1, 29.8, 25.7, 23.1, 14.3ppm.

Mass spectrum (silylated): m / e = 928
(M ⁺ ), 913, 901, 837, 823, 793, 745, 624, 611, 53
9, 493, 449, 359, 91.

Production Example 9a N, N'-dibenzyloxycarbonyl-6 '
-Propylspectinomycin A solution of N, N'-dibenzyloxycarbonyl-2'-o-acetyl-4 ', 5'-didehydro-6'-propylspectinomycin (0.70 g) in tetrahydrofuran (10 m
It was dissolved in l) and cooled to -78 ° C. A 1 molar solution of tri-sec-butyllithium borohydride in tetrahydrofuran (3.0 ml) was added. After stirring under nitrogen at -78 ° C for 25 minutes, the solution was diluted with ethyl acetate (10 ml) and acetic acid (0.2 ml).
It was poured into a mixed solvent of. Furthermore, ethyl acetate (10m
l), water (1.0 ml) and triethylamine (1.0 ml) were added. After 2 hours additional triethylamine (1.0 ml) was added and the solution was stirred at room temperature for 16 hours. Skellysolve B (20 ml) and saturated aqueous sodium bicarbonate solution (15 ml)
Was added and the phases were separated. The upper phase was saturated with NaCl (15m
l) washed. The organic phase was concentrated with sodium sulfate to a dry oil. This was chromatographed on silica gel (40 ml) filled with methylene chloride. The product is methylene chloride (50 ml), methylene chloride / chloroform 1: 1 (60 ml), chloroform (50 ml), 0.5% methanol / chloroform (100 ml), 1% methanol / chloroform (100 ml), 2.5% methanol / chloroform (100 ml). ) And 5% methanol / chloroform (200m
l) was eluted. Concentrate appropriate fractions to concentrate N, N'-
0.45 g (68.3%) of dibenzyloxycarbonyl-6'-propylspectinomycin was obtained.

Using N, N'-dicarbobenziloxy-6'-octylspectinomycin in place of N, N'-dicarbobenziloxy-6'-alkylspectinomycin, which is appropriately substituted, as in Preparation 9 or 9a 6'by the same method
-Alkyl spectinomycins were obtained.

N, N'-dibenzyloxycarbonyl-6'-ethylspectinomycin; CMR 201.0, 158.2, 138.2, 129.1, 128.4, 97.6, 92.
3, 75.2, 74.7, 74.6.71.5, 67.2, 66.2, 65.6, 61.1,
60.2, 57.6, 57.3, 44.1, 38.2, 31.7, 31.4, 18.2, 1
4.1 ppm.

N, N'-dibenzyloxycarbonyl-6'-n-propylspectinomycin; CMR 201.8, 156.7, 138.1, 129.1, 128.3, 97.5, 92.
3, 75.1, 74.7, 74.6.71.8, 67.2, 66.4, 65.6, 60.9,
59.9, 57.5, 44.1, 35.7, 31.4, 30.8, 27.7, 23.0, 1
4.2 ppm.

N, N'-dibenzyloxycarbonyl-6'-n-butylspectinomycin; CMR 201.5, 156.2, 138.2, 129.4, 128.6, 97.7, 92.
6, 75.3, 75.1, 74.8.72.1, 67.6, 66.7, 66.0, 61.0,
60.0, 57.8, 44.3, 35.3, 31.6, 32.5, 32.1, 31.8, 3
1.2, 30.2, 29.2, 25.6, 23.3, 14.6ppm.

N, N'-dibenzyloxycarbonyl-6'-isobutylspectinomycin; N, N'-dibenzyloxycarbonyl-6'-n-pentylspectinomycin; CMR 202.0, 158.1, 138.2, 129.1, 128.4, 97.6 , 92.
4, 75.2, 74.6, 74.0.71.8, 67.2, 66.4, 65.7, 61.1,
60.1, 57.5, 57.3, 44.1, 36.1, 32.3, 31.7, 31.4, 2
9.7, 25.6, 23.2, 14.3 ppm.

N, N'-dibenzyloxycarbonyl-6 '-(3,3-dimethyl) -n-butylspectinomycin; N, N'-dibenzyloxycarbonyl-6'-cyclopentenyl spectinomycin; N, N '-Dibenzyloxycarbonyl-6'-cyclohexylmethylspectinomycin; CMR 202.0, 157.5, 138.0, 129.1, 178.3, 97.5, 92.
3, 75.1, 74.7, 72.1.67.2, 66.4, 65.6, 60.9, 60.7,
57.5, 57.3, 44.1, 38.2, 33.8, 33.5, 31.7, 31.4, 2
7.2, 26.9 ppm.

N, N'-dibenzyloxycarbonyl-6'-undecylspectinomycin; and 6'-n-butylspectinomycin analogs of Tables XVII and XVIII.

Example 1 6'-n-octyl spectinomycin N, N'-dibenzyloxycarbonyl-6'-n-octyl spectinomycin (0.09 g) in methanol (7.0 ml)
And was stirred in a nitrogen atmosphere. Palladium black (60 mg) was added followed by 97% formic acid (0.45 ml). After stirring thoroughly for 40 minutes, the catalyst was passed through and the solution was concentrated in vacuo.
The residue was taken up in H ₂ O (8 ml) and 0.1 N HCl (0.35 ml)
It was acidified to pH 1.5. The sample was freeze-dried to prepare a CMR sample. After CMR, the sample was diluted with H ₂ O and lyophilized to give 6'-n-octylspectinomycin dihydrochloride 0.05 g.
Got

CMR (for D ₂ O, internal CH ₃ CN): 92.9, 92.6, 91.1, 7
0.9, 68.8, 65.1, 64.7, 60.6, 58.7, 57.5, 38.2, 33.
4, 30.8, 30.1, 29.5, 28.5, 28.2, 24.2, 21.5, 12.8p
pm.

Using N, N'-carbobenziloxy-6'-n-octylspectinomycin in place of the appropriately substituted protected 6'-alkylspectinomycin as the dihydrochloride salt in the same manner as in Example 1. The following 6'-alkylspectinomycins were obtained.

6'-Ethylspectinomycin; CMR 29.8, 29.4, 60.6, 58.6, 57.6, 64.6, 70.7, 65.
0, 92.7, 92.7.91.0, 58.5, 68.8, 35.0, 16.6, 12.4pp
m.

6'-n-propylspectinomycin; CMR 29.8, 29.4, 60.6, 58.6, 57.6, 64.6, 70.9, 64.
9, 92.6, 92.6, 91.0, 38.5, 68.7, 32.5, 25.4, 21.
0, 12.3ppm.

6'-n-butylspectinomycin; CMR 29.9, 24.4, 60.4, 58.5, 57.4, 64.5, 70.7, 64.
9, 92.5, 92.5.90.9, 38.7, 68.7, 32.9, 30.1, 23.1,
20.4, 12.5ppm.

6'-isobutylspectinomycin;6'-n-pentylspectinomycin; CMR 29.8, 29.3, 60.6, 58.6, 57.7, 64.7, 71.0, 65.
0, 92.7, 92.7, 91.1, 38.6, 68.8, 32.9, 30.1, 23.
2, 21.0, 20.8, 12.5ppm.

6 '-(3,3-Dimethyl) -n-butylspectinomycin; 6'-cyclopentylmethyl spectinomycin; 6'-cyclohexylmethyl spectinomycin; CMR 30.1, 29.5, 60.6, 58.6, 57.5, 64.7, 70.9 , 65.
1, 92.6, 92.6, 91.1, 38.2, 68.8, 33.4, 30.7, 28.
5, 28.5, 28.2, 28.2, 24.2, 21.5, 12.8ppm.

6'-n-undecyl spectinomycin; and CMR 60.5, 58.6, 57.5, 64.9, 70.9, 65.2, 97.7, 92.
8, 91.2, 38.8, 68.8, 33.4, 30.9, 28.4, 28.8, 28.
8, 28.8, 28.8, 28.8, 28.8, 24.4, 21.5, 12.8, 30.
2, 24.6ppm.

6'-n-octylspectinomycin analogs of Tables XIX and XX.

Example 2 6'-n-Propylspectinomycin Sulfate N, N'-Dibenzyloxycarbonyl-6'-n-propylspectinomycin (2.20 g) in methanol (100 ml)
And was stirred in a nitrogen atmosphere. Palladium black (1.39 g) was added followed by 97% formic acid (4.3 ml). After thorough stirring, the catalyst was passed and the liquid was concentrated in vacuo. Residue
Take up in H ₂ O (10 ml) and a 1 molar sulfuric acid solution (3.5 ml)
Acidified with. The sample was lyophilized and then recrystallized from acetone: water to give 0.87 g of 6'-n-propylspectinomycin sulfate pentahydrate.

CMR (for D ₂ O, internal CH ₃ CN): 118.07, 92.67, 91.24, 91.06, 70.73, 68.94, 65.01,
64.74, 60.78, 59.15, 57.69, 38.77, 32.83, 30.35, 2
9.77, 25.78, 21.18 and 12.45 ppm.

Claims (5)

[Claims] Claim: (a) Formula IV: Reacting a compound of formula III with an alkylmagnesium halide having the formula R′MgX, where X is halogen, (B) reacting the compound prepared in step (a) with a reducing agent to give a compound of formula II: And the protecting group of the compound prepared in step (b) is removed to yield a compound of formula I: A process for the preparation of a compound of formula I above, which comprises preparing a compound of formula I, optionally a hydrate thereof or a pharmaceutically suitable salt thereof. (In the above formulas, R is hydrogen or lower alkyl; R '
Is a linear or branched alkyl group having 1 to 18 carbon atoms, or an alkyl group of a cyclic chain, wherein the longest extension of the branched or cyclic chain contains 1 to 4 carbon atoms; R ₁ ~ R ₉
Selected from _{R '2, R' 3,} R '6 and R' ₇ is lower alkyl, lower alkenyl, the group consisting of lower alkynyl and a protecting group; is hydrogen, lower alkyl, selected from the group consisting of lower alkenyl and lower alkynyl And said protecting group is selected from the group consisting of aralkoxycarbonyl, alkoxycarbonyl halides and alkoxycarbonyls; provided that one of R ₂ and R ₃ is always hydrogen.
One of R ₆ and R ₇ is also always hydrogen, and one of R ₂ ′ and R ₃ ′ is always a protecting group and R
₆ 'and R _7' have always protecting groups one of; R ₁₀
Is acyl; A is selected from oxygen and sulfur; and B and B ₁ are the same or different and are hydrogen, hydroxy,
It is selected from the group consisting of alkoxy, o-lower alkenyl, thiol, thio-lower alkyl and thio-lower alkenyl. ) 2. The method according to claim 1, wherein the compound produced is selected from the following compound group. 6'-ethyl spectinomycin, 6'-ethyl spectinomycin dihydrochloride, 6'-n-propyl spectinomycin, 6'-n-propyl spectinomycin dihydrochloride, 6'-n-propyl Spectinomycin / sulfate, 6'-n-butyl spectinomycin, 6'-n-butyl spectinomycin / dihydrochloride, 6'-iso-butyl spectinomycin, 6'-iso-butyl spectinomycin Dihydrochloride, 6'-n-pentylspectinomycin, 6'-n-pentylspectinomycin, dihydrochloride, 6 '-(3,3-dimethyl) -n-butylspectinomycin, 6'- (3,3-Dimethyl) -n-butylspectinomycin dihydrochloride, 6'-cyclopentylmethylspectinomycin, 6'-cyclopentylmethylspectin Nomaishin dihydrochloride, 6'cyclohexylmethyl spectinomycin and 6'cyclohexylmethyl Spectinomycin dihydrochloride. 3. A compound of the following formula, a hydrate thereof or a pharmaceutically suitable salt thereof. (In the formula, R is hydrogen or lower alkyl; R ′ is a straight-chain or branched-chain alkyl group having 1 to 18 carbon atoms or a cyclic-chain alkyl group; The longest extension comprises 1 to 4 carbon atoms; R _{1 to} R ₉ are selected from the group consisting of hydrogen, lower alkyl, lower alkenyl and lower alkynyl; A is selected from oxygen and sulfur; and B and B ₁ is the same or different and is selected from the group consisting of hydrogen, hydroxy, alkoxy, o-lower alkenyl, thiol, thio-lower alkyl and thio-lower alkenyl.) 4. A compound according to claim 3 having the following formula, a hydrate thereof or a pharmaceutically suitable salt thereof. (Wherein R ″ is selected from the group consisting of ethyl, n-propyl and n-butyl; R ₂ , R ₃ , R ₆ and R ₇ are selected from the group consisting of hydrogen, lower alkyl, lower alkenyl and lower alkynyl. Where one of R ₂ and R ₃ is always hydrogen and R ₆ and
One of R ₇ is also always hydrogen; A is selected from oxygen and sulfur; and B and B ₁ are the same or different and are hydrogen, hydroxy, alkoxy, o-lower alkenyl, thiol, thio-lower alkyl and It is selected from the group consisting of thio-lower alkenyl. ) 5. The compound according to claim 3, which is selected from the following compound group. 6'-n-propyl spectinomycin, 6'-n-propyl spectinomycin dihydrochloride, 6'-n-propyl spectinomycin sulfate, 6'-n-butyl spectinomycin, 6'- n-butyl spectinomycin dihydrochloride, 6'-iso-butyl spectinomycin dihydrochloride, 6'-iso-butyl spectinomycin dihydrochloride, 6'-n-pentyl spectinomycin, 6 '-(3 , 3-Dimethyl) -n-butylspectinomycin, 6 '-(3,3-dimethyl) -n-butylspectinomycin dihydrochloride, 6'-cyclopentylmethylspectinomycin, 6'-cyclopentylmethylspectin Tynomycin dihydrochloride, 6'-cyclohexylmethyl spectinomycin, 6'-cyclohexylmethyl spectinomycin dihydrochloride , 6'-n-undecyl spectinomycin, and 6'-n-undecyl spectinomycin dihydrochloride.