JPS58135889A - Production of alpha-substituted ureidobenzylpenicillanic acid - Google Patents

Abstract

PURPOSE:The reaction between N-benzoylcarbamic acid halide and alpha-aminobenzylpenicilline is followed by deprotection to give the titled compound useful as an antibacterial against gram-positive and -negative bacteria and Pseudomonas bacteria. CONSTITUTION:An N-benzoylcarbamic acid halide of formulaI(R8 is protected hydroxyl; X is 1-5C alkyl; Y<2> is alkoxy, cyano, ester; Z is halogen) is made to react with an alpha-aminobenzylpenicilline of formula II (R<11> is H, hydroxyl, protected hydroxyl; R<7> is H, protecting group) or its reactive derivative, then, when there are protecting groups in the product, they are removed to give the objective compound of formula III (R<1> is H, hydroxyl, Y is Y<2>) or its pharmacologically permissible salt.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the general formula (1) (wherein, V represents a hydrogen atom or a hydroxyl group,
The lower alkyl group, and the lower alkyl group of substituents O1-4 of yFix, and the lower alkanoyl group 1+ of Ot-4 are substituted with a hydroxyl group or a lower alkoxy group of 01-4 0! -4 lower alkyl group, R3 is hydrogen atom or 01-4 lower alkyl group, R4 is hydrogen atom, nitro group is 01-4 lower alkoxy group, ・R5 is hydroxyl group, 9 is 4- ooo♂ (81 is the same as above),
For duck, if Y is a base 10-), enter 2, if it is another group, enter l, *tfle2t or 3, and for shyness, enter 0.
．． 1. It means 3 times the goose. ) Compound f represented by
& relates to a pharmaceutically acceptable salt thereof.

The --W-diuretbenzylpenicillin represented by the above general formula (1) is a new compound not yet described in the literature, and it exhibits strong antibacterial activity against Gram-positive and Gram-negative 11. It is characterized by its strong anti-activity against Domonas sp. and its superior in vivo activity compared to conventionally known compounds. That is, the compound represented by the above general formula (summer) and its pharmaceutically acceptable salts are useful as a pickling agent.

Thus, an object of the present invention is to provide an excellent anti-monostatic compound represented by the general formula (1) and a pharmaceutically acceptable salt thereof.

1 In formula (1), a lower alkyl group as meant by X, a lower alkyl group, a lower alkanoyl group, and a lower alkoxy group included in the definition of In other words, the lower alkoxy group in ξ is a saturated hydrocarbon group that is bent and branched in Jikidan.

The number of carbon atoms in the lower alkyl group represented by X is:
When the substituent Y means +OR") m, it is selected from the range of 2 to 5, and when Y means a group other than +0♂), that is, the group -ON, -000, it is selected from the range of 1 to 5. selected from the range.

Substituent Y in the lower alkyl group represented by X
The position of 1 to st+ may be in the position of 2 to 5 carbon atoms.

Since the α-substituted ureidobenzylpenicillins according to the present invention have a YK carboxyl group at the 3-position and in some cases, the α-substituted ureidobenzylpenicillins can form salts with various basic substances at the 3-position, and are pharmaceutically acceptable. Salts with soluble basic substances are superimposed.

Examples of such salts include salts of inorganic bases, salts of alkali metals such as sodium and potassium, salts of alkaline earth metals such as calcium, and salts of organic bases such as procaine and dibenzylethylenediane. A platform will be raised.

These salts can be prepared by conventional methods, ie by treating the mosquito carboxyl group with an equimolar amount of the above-mentioned abutment groups.

Optical isomers exist in the compounds of the present invention due to the asymmetric carbon atom in the 6-acedoradical group.

DL-, D- and L-isomers, - may sometimes exist as lydiastereomers, and all of these are included in the scope of the present invention.

The compound represented by the general formula (1), α-substituted ureidobenzylpenicillins, can be produced by various methods.

For example, general formula < If K is the same as Y, it means that if there is a hydroxyl group or carxyl group in Y, it (etc.) is retained.X is the same as above. ) and a reactive derivative of monomer-substituted ureidophenylacetic acid or its 1, represented by the general formula (in the formula, R1 represents a water-reducing group or a group). 6-amitubenicilanic acid, represented by R'', R', R't or Yl
If the compound has a protecting group, this production method is characterized by removing it (and so on).

In the general formula (■), BIS, R@ and Y'Kt
In rare cases, the protecting group for the hydroxyl group may be any group that can be easily removed under mild conditions, such as formyl group, acetyl group, glopionyl group, butyryl group, acyl group such as chloroacetyl group, benzyl group, benzhydryl group, Aralkyl groups such as the trityl group, firstly a methoxy group on their allyl nucleus, secondly a substituted aralkyl group having a substituent of the El group, trimethylsilyl group, triethylsilyl group, dimethylmethoxysilyl group, diethylmethoxysilyl group, Mention may be made of the supporting groups #$ commonly used for hydroxyl groups such as methoxysilyl group, triethoxysilyl group O, and tetrahydropyranyl group.

In addition, the protecting group of carboxylic acid contained in Y''K is.

Talolomethyl group, λλ2-trichloroethyl group, 2.1
A halogenated lower alkyl group such as a 2-trialoloethyl group, an aralkyl group such as a benzyl group, a benzhydryl group, a trityl group, or a substituted aralkyl group having a substituent such as a methoxy group or a nido group on the allyl nucleus thereof. It is possible to build a foundation of humanity.

In the reactive derivative of α-substituted phenyl acetate represented by the general formula (letter), the carboxyl group involved in the reaction is activated and forms a trace line in the conductor.

For example, they include Shun anhydride, active ester, active amide, acid halide, and the like.

Specific ILs For example, mixed anhydrides with aliphatic carboxylic acids such as piparic acid, trichloroacetic acid, and pentanoic acid; alkyl carbonic acid mixed anhydrides; phenylphosphoric acid mixed anhydrides; aromatic carboxylic acid mixed anhydrides; 1-hydroxybenzotriazoli Imidazole, triazole, tetrazole and O acid Amide et al.

In addition, when R7 is a protecting group, especially a group that can constitute an ester, the ad-bond formation reaction does not lead to the substituted ureidophenylacetic acid into a reactive derivative, but instead leaves the carboxylic acid as it is. , N'-dicyclo to now zylcarboxylic acid,
N, N'-diethylcarbosylf)', N-cytalohene N'-morpholinoethylcarposiindo, N,
N'-diinopropyl carbide can be efficiently carried out using carbodiimides such as di-ξ-d as a condensing agent.

1! In general formula (1) Kbh-c, R'l, vPbx
When all of the hydroxyl groups and carboxyl groups contained in fK and fK are protected, α-substituted ureidophenylacetic acid can be subjected to the reaction in the form of a halide. A method of introducing an acid halide and reacting with a commonly used halogenating agent such as oxuryl chloride, thionyl chloride, or dimethylformanilide and N-methylformanilide and thionyl chloride, For phosphorus oxychloride and trichloromethyl chloroformate, a method is used in which a Vilsmeier reagent obtained by reaction with phosgene or the like is used.

R of 6-adenobenicilanic acid represented by general formula (1)
When 7 is a protecting group, as an example of a yibao group, alkali 1
Inorganic bases that can form salts of metals, alkaline earth metals, triethylamine, N-methylpiperidine, pyridine, etc. are organic bases, 4-methyl group, 112-tritalotetraethyl group, 2,2,2-trifluoro group. halogenated lower alkyl groups such as ethyl group, benzyl group, benzhydryl group,
Aralkyl groups such as trityl groups include substituted aralkyl groups having a substituent such as methoxy group or nitro group on their allyl nucleus, trimethylsilyl group, triethylsilyl group, dimethylmethoxysilyl group, diethylmethoxysilyl group. , a trimethoxysilyl group, a silyl group such as a triethylsilyl group, and the like.

9. The reactive derivative of 6-amitubenicilanic acid is:
It means a derivative in which the 6-amino group is activated. Activation is carried out, for example, by the introduction of a silyl group such as a trimethylsilyl group.

The AND bond forming reaction is preferably carried out in a solvent,
As a solvent, acetone, tetrahydro7rane, dimethylformad, pyridine, acetonitrile, dioxane, dichloroform, dichloromethane, dichloroethane,
An inert solvent such as ethyl acetate is used. Among these, hydrophilic solvents can also be used in combination with water.

The reaction is usually carried out under cooling or at room temperature, but may also be carried out under heating. That is, the temperature is usually selected from the range of -30 to 30°C, but preferably 0 to 10°C when the a-substituted ureidophenylacetic acid is used in the form of an active ester and an active and, and preferably 0 to 10°C when it is used in the form of an acid anhydride. is -1
5 to -5°C, and -20 to -10°C when used in the form of a warm halide.

The reaction time varies depending on the reaction temperature, the compound used in the reaction, the solvent, etc., and is normally selected as appropriate within the range of 0.5 to 48 hours, preferably 1 to 24 hours.

After carrying out the AND bond-forming reaction, if the product has a protecting group, it is removed.

In the case of an acyl group, the protective group of the hydroxyl group contained in -1R6 and YIK can be removed by treatment with an inorganic or organic base. Examples of the inorganic base include sodium hydroxide, potassium hydroxide, etc. Unoxidized alkali gold column, magnesium hydroxide.

Alkaline earth metal hydroxides such as calcium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, carbonic acid! Alkaline earth metal carbonate salts such as gnesium and calcium carbonate, and sodium hydrogen carbonate.

Examples include alkali metal bicarbonates such as potassium hydrogen carbonate, alkaline earth metal phosphates such as calcium phosphate, alkali metal hydrogen phosphates such as dipotassium hydrogen phosphate, dipotassium hydrogen phosphate, ammonia, etc. Examples include alkali metal acetates, trimethylane,
Examples include trialkylamines such as triethylamine, diethylaminoethanol, and triethanolamine-based alcohol bases. Removal of the acyl group with a base such as water or an organic solvent containing an alcoholic hydroxyl group (e.g., methanol, ethanol).

The method is carried out using ethanol (ethanol) or a mixture thereof. Preferred examples include methanolic ammonia and a triethylamine-triethanolone-dimethylformamide mixture.

When the S-carrying group is an aralkyl group or a substituted aralkyl group, removal can be carried out by catalytic reduction, for example using palladium carbon. Furthermore, -
-Butyl groups, methoxymethyl groups, phenacyl groups, tetrahydropyranyl groups and silyl groups can be removed using an inorganic acid such as hydrochloric acid.

In the case of a halogenated lower alkyl group, removal of the carboxyl group contained in the YIK and the ζ-carrying group by R1 can be carried out by reduction with a metal and an acid, such as zinc-acetic acid, or an aralkyl group. and substituted aralkyl groups by catalytic reduction, e.g. with p-5-carbon, or by ion exchange, e.g. with formic acid, trifluoroacetic acid, benzenesulfonic acid, hydrochloric acid, ion exchange This can be carried out using a resinous organic or inorganic acid or a Lewis acid such as aluminum chloride, and the silyl group can be treated with the above-mentioned acids or an alcohol such as methanol. Can be easily removed
If BY is a salt-forming salt straw, it can be removed by treatment with acid.

Isolation and purification of the target product from the reaction mixture can be easily carried out according to conventional methods. For example, dichloromethane, tetraform, and tetrahydrofuran.

Extraction with ethyl acetate and organic solvents, or various chromatography methods using activated carbon, silica gel, ion exchange resin, dextran sa polymer, porous polymer of styrene-divinylbenzene or acrylic ester, etc. You can do it by doing this.

α-Substituted ureidophenylacetic acid represented by the above general formula (厘) is a new compound, but for example, the corresponding a-a2
Produced by reacting nophenylacetic acid with an N-substituted benzoyl-N-substituted alkylcarbanic acid halide in which the hydroxyl group and carboxyl group are retained, and then removing the protecting group if necessary. can do.

Protecting groups used herein and their means of elimination.

The protecting groups for R@, Bll and Yl are described above.

Another method for producing the compound represented by the general formula (1), α-substituted ureidobenzylpenicillins, is the compound represented by the general formula (M) 1. - is YK
In the corresponding group, when a hydroxyl group or a carboxyl group is present, it means a group in which the carboxyl group (etc.) is protected. Means two halogen atoms. )
- A benzoylcarpainic acid halide is reacted with an 1-ainobenzylpenicillin represented by the general formula (V) (wherein -1 and R7 are the same as above) or a reactive derivative thereof, and then the product is This method is characterized by removing existing protecting groups.

In the general formula (W), the protecting groups 8 and yJct are the same as those described in 9 for I and Q. The reactive derivative of α-adenopenzylbenicine represented by the general formula ff) is a derivative in which the α-aino group is activated, and the activation is caused by the activation of the α-aino group. This is done by introducing a silyl group such as a trimethylsilyl group into the polymer.

The reaction is preferably carried out in a solvent, and examples of the solvent include a7ton, tetrahydrofuran, acetonitrile, dimethylbormamide, and pyridine.

Inert organic solvents such as dioxane, chloroform, dichloromethane, dichloroethane, and ethyl acetate are used. Among these, hydrophilic solvents can also be used in combination with water.

The reaction is usually carried out under cooling or heating, preferably at a temperature of 0 to 30 DEG C., and the time period of 0 to 1 hour is usually selected in the range of 1 to 48 hours, preferably 1 to 10 hours.

Removal of protecting groups present in the product is performed using Bll, B@
.

Same procedure as described for removal of R7 and Yl protecting groups.
Purification is carried out by the same means as described in 9 above.

N-benzoylcarbamic acid halides represented by general formula (II) are new compounds, but when the corresponding penza ζ-do or its derivative is mixed with phosgene, trifluoromethyl chloride, etc. in an organic solvent such as dichloromethane, tetrahydrofuran, or ethyl acetate. It can be prepared by reacting a carbonylating agent such as formate.

The optical isomer, which is a type of α-substituted benzylpenicillin m represented by the general formula (Natsu), can be produced by using α-substituted ureidophenylacetic acid having the desired optical activity (general formula From Jin and K using χ--benzylpeecillin II (-1r formula (V)),
Also the desired diastereo! -N-benzoylcarbanoic acid halides (general formula (
*) By using ), this can be done efficiently. The above-mentioned optically active substance can be obtained by applying ordinary optical resolution techniques.

The object compound of the present invention, i.e., the compound represented by the general formula G) and its pharmaceutically acceptable salts, can be formulated into forms 111 suitable for various administration methods, as in the case of other penicillin compounds.

Accordingly, in embodiments of the present invention, human or veterinary medicine compositions are provided in a conventional manner using the necessary pharmaceutical carriers or excipients, i.e., as injectable compositions. When provided, they can take the form of suspensions, solutions, and emulsions in oily or aqueous vehicles.

Suppositories can also be made, and conventional suppository substrates such as cocoa milk fat or other glycerides can be used.

These compositions may contain 0.1% or more of active substance, such as from 5 to 99%, preferably from 10 to 60%, depending on the method of administration.

H) The dose for K is usually 100 to 300 for adults.
Selected within the range of 0'IQ. For example, 500 to 200 doses per day depending on the administration route, frequency, body weight, age, and tree shape.
A dosage of G''F is a preferred example.

To summarize the pharmaceutical characteristics of the compounds for the purpose of the present invention, some of them are shown in terms of minimal inhibition of growth (MIO, sy/d) for various 111 IKs and for domonas l! in mice. Results of infection treatment experiments for IK (
lDl・)t, 6-(D(-)-α-(4-ethyl-
2,3-dioxo-1-piverazinylcarbonyla)
) quenylacetamide] penicillanic acid (generic name Bibettalin) and 6-(D(-)-α-(3-(3,
4-dihydroxybenzoyl)-3-methyl-1-ureido)-α-phenylacedo]penicillanic acid (hereinafter also referred to as compound Z).

(described in West German patent publication Ak2921324).

1. MIO measurement results (1) Test method The following agar plate multiple dilution method Kjl test tube pile - To measure the activity, for Heart Influenza - Cultivate overnight in Divin Pross and dilute 100 to 1000 times. One platinum loopful of each test strain was inoculated into Heart Inn 7-Diben Agar (HI Amten) containing each me compound, cultured at 37°C for 20 hours, and M10t11iII was determined.

12) Results No. 1 (A) showing the test compound shown in Table-1.

B, ...) correspond to the symbols in the examples (the same applies below).

λl D l @ Measurement results (1) Test method Six male mice of the 251 Foddy strain, 5 weeks old and weighing 2 liters, were used as one group. Above, nine specimens were cultured overnight at 37°C, suspended in 5% mucin, and administered intraperitoneally to mice.

Test compounds can be prepared at various times and injected subcutaneously into mice - 01 and 3 hours after inoculation, and after 5 days, ID values were calculated from the number of surviving mice at each dose.

Compensation test results Table 2 shows the test results.

The results show that the target compound of the present invention has excellent in vitro and in vivo activity.

Examples are given below to specifically explain the method for producing the target compound of the present invention.

Example 1゜(1) N-(3-human tetraxiptetrapyr)-tortoise 4-dihydroxybenzaelectrode5. Dry dichloromethane 770m011 containing Of and trimethylsilyltalolide 119F
1Ws liquid K) 'Jz + Lua t7t 1.5ft included t
40 ml of dry dichloromethane solution are added dropwise under ice-ice cooling. The mixture is heated in a nitrogen atmosphere for 40 minutes, and then, under cooling, triter-tetramethylchloroformate (Lad) is added dropwise at -10 to -5°C.

Gradually raise the liquid temperature and stir at 0 to 5℃ for 2 hours.
The excess phosgene and solvent are distilled off under reduced pressure. After cooling, 80 d of nine-dried dichloromethane was added to the residue, insoluble materials were removed by natural filtration, and the mixture was subjected to the reaction described below.

(2) Anhydrous ampicillin 1a8f and triethylamine 7
A dry dichloromethane solution containing 1F 100 dK trimethylsilyl chloride 7.81 is added dropwise at 5-10°C.

Stir at the same temperature for 1 hour, and add dropwise to a 9-dichloromethane solution prepared using the above-mentioned sweetfish (1) while stirring at ~5°C. 5～
After heating at 10℃ for 1 hour, evaporate to dryness at room temperature under reduced pressure, and add 300ml of ethyl acetate and 100ml of cold 6N acid to the residue.
Add the mixture of d and separate the organic layer. The organic layer was washed with 300ml of cold saturated brine, and then washed with 90ml of cold saturated sodium bicarbonate solution.
Separate and wash the aqueous layer with 100 ml of ethyl acetate, add 250 ml of ethyl acetate to this, adjust the μ value to about L5 with cold 6N acidic acid, and Add salt to saturate the aqueous layer, and then separate the organic layer. The organic layer is washed with cold saturated brine 100111, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue is subjected to column chromatography on activated carbon (for lithography) and eluted with ethyl acetate. #! The effluent was collected and concentrated under reduced pressure in a trench with a liquid volume of about 30 dK, and then added to a 300-d container with stirring to give 6-(D (-)-α-(3-(3, 4-dihydroxybenzoyl)-3-(31:I'0+/pw
pill)-1-ureido)-α-phenylacedore]
Penicillanic acid (hereinafter also referred to as compound A) a, Ot is obtained as a white powder.

I Rw ”' (as ”) ” 3700~23
00 * Z 775-111 1m$75.1600.1515 N M & (DM80-dge 60MHz) a
(p): 141 (3H.

s) #155 (3He s) s L4~2
．． 0 (2H# b r ) e136(!H, 1, J
-6Hz), 175 (2H, br).

410 (IH, s), 13-5.8 (3H, @l)
, 6.7-7.5 (8H, s), 9.2 (Ten H, br)
U V J”oiiwa(#)s209(&1xlO
'), 295 (sS# m3X1♂), 225 (shoulder), 27111XIO'') Ferric chloride color reaction: Positive (dark green) (a) In Example 1 (1), )-3,4-dihydroxybenzamide 5, O
KN-(5- and droxypentyl) in place of f -3,
When 4-dihydroxybenzamide 5.0f is used and treated in the same manner, 6- (T) (-) -α-(3-(
3,4-dihydroxybenzoyl)-3-(5-and droxypentyl)-1-ureido)-α-phenylacetamide] penicillanic acid (hereinafter also referred to as compound 0) &2t
is obtained as a white powder.

I Ry"'(or') @3700-1200.17
70°Tsuru a! 1 1675.1600.1515 N M R (DM80-d@, 60MHg) a (
FP): L3 (8H.

brs), 1.41 (3H, s), 1.55 (3H,
m),! L1~1G (4H, gift), 4jl (IH, s
), 53~8 (3B, s), &7~7.5 (
81H, s), 9.14 (IH.

d, J=7Hg), 9.24 (IH, d, J-
7Hz) U V J 2"az -(')"
207 (L 2 × 10') -225 (shoulder),
272 (tOXlG"), 293C43XlG") Ferric chloride color reaction window positive (dark green) (b) Substitute for N-(3-hydroxypropyl)-&4-dihydroxybenzamide 5, Of in Example 1 (1) KN-(2-(2-hydroxyethoxy)ethyl)-3,4-dihydroxybenzamide5. Using Of and processing in the same way below, we get 6- (D (-) -a -
(3-(turtle 4-dihydroxybenzoyl)-3-(2-
(2-and droxyethoxy)ethyl)-1-ureido]
-α-phenylahydramide] penicillanic acid (hereinafter also referred to as compound Ri) 5.2F is obtained as a white powder □
.

■ "H Niji (ai') g 3700~2
200. 1 775°1g75.1600.1515
,105ON MB (DM80-4!60MHg)
'(P)! 1.41 (3H.

s), L55 (3H, s) #&3~tl (8Hr++
a) #4.20 (IH, a), 5.3-5.8 (3
H,s), 6.7-7J(aH,s), 9.08(
IH, d, J-7H fable).

91G (11 (, d, J-78g) U V JL # ss (' ) ” 207 (1
g ×10') -224 (shoulder),! 7G (4,6X1
295 (t6 ,ot
5. N-(2-methoxyethyl)-λ4-dihydroxypendazole instead of o. of and trimethylsilyl chloride at 9.7F.

When triethylamine is treated in the same manner using &6F, 6-CD (-)-α-[3-(turtle 4-dihydroxybenzoyl)-3-(2-methoxyethyl)-1-ureido)-α1-phenyl Penicillanic acid (hereinafter also referred to as compound E)? ,
Of is obtained as a white powder.

I R#IKB'(j”)!3700~2300.1
775゜嘱11II1 1675.1600.1515.1055N M R(
DM80-ds, 60MHg) J (FFI): L4
1 (38°i), 1.56 (3H, s), 3.18 (
$1(,s).

3.40 (2H, br), 185 (!H, br), humiliation 420 (IH, a), &3~5.8 (3H*s) * 6.7~7.6 (881 inertia) # Q
, 11 (IHmd, J=7Hg), 9.1S (IH, d
, J-7Hg)UVλ”,”Fsm(o = 208(
18X10'), 2!4 (1111) #272 (5,9
X10''), 295 (S, 9X1O'') Ferric chloride color reaction = positive (dark green) (d) In Example 1 (1), N-(3-hydroxypropyl)-3,4-dihydroxybenzamide lof N-(2-cyanoethyl)-tortoise 4-dihydroxybenzamide 4. Of 1, and trimethylsilylchloride t-7,9F,) ethylamine to 71f
6- (D (-)-α
-(3-(3,4-dihydroxybenzoyl)-3-(
2-cyanoethyl)-1-ureido)-α-7enylaceto]penicillanic acid (hereinafter also referred to as compound F) t
Of is obtained as a white powder.

I Rp"'(j"); 3700-2300.220
G.

4- 1γ70.1685.1600,151ON M R (
DM80-d@, 60M) Is) J(-): L41
(3H.

s), L55 (30, i), 2.78 (2H, br),
3.98 (2H, br), 4.20 (IH, a), &3
~18 (3H, *) , &? ~7.5 (8H, s),
9.09 (18.4J=7Hm), 9.14 (1
)I, d, J-7Hz) UVλ”0Has(#)
:207 (18X10'), 226 (shoulder).

Chi-Ill 276 (&lX10"), 295 (!L5X10") Ferric chloride color reaction: Positive (dark green) P-4-dihydroxybenzamide S, O
N-ethoxycarbonylmethyl-3,4- in place of t
Syhydro-dibenzamide &5^, and trimethylsilyl chloride at 5.9f,) ethylamine at &3
Using 6-CD(-)-1-(
3-(&4-dihydroxybenzoyl)-3-ethoxycarbonylmethyl-1-ureido)-α-phenylacetamide penicillanic acid (hereinafter also referred to as compound G) 4
．． Of is obtained as a white powder.

I Ry: 2 (am-'): 3700-2200.1
7?0°1730.16g5.1600.1515N
M B (DM80-ds, 60MHi) J(P):L
O~1.4 (3H.

sacrifice), 1.40 (3H, s), 1.55 (31 (, m
), 18-4.6 (4H, @), 4.20CIH, @
), 5.3~5J(3H,s), 6.7~7.6(
8H, s), 9.22 (IH.

d, J=7Hg), 9.47(IH,d, J=7
Hs) UVλ,,, wa(#): 20g (15X10'
), 22g (shoulder 125g (4,8X10”), 294
(4,8X10”) Ferric chloride color reaction: positive (dark green) (f) Example 1 (1) N-(3-hydroxyptetravir)-tortoise 4-dihydroxybenzamide LOPO in 4C
%N-benzyru-3.4-dihydro-tetraxybenzado in place of 9.5. Of and trimethylsilyl chloride at 8.4f,) ethylamine at 7. Using SF, the following uniform processing yields 6- CD (-) -g -(3-
(turtle 4-dihydroxybenzoyl)-3-benzyl-1
-Ure(1-11 phenylacetoad)penicillanic acid (hereinafter also referred to as compound H) 4. Of is obtained as a white powder.

IRν"'(tx-"=3700~2200.1770
゜Cod 16110.1600.151O N M R (DM80-d@, 60MHz) '(P)
: L42 (3H.

s), L55 (3H, s), 4.21 (IH, s), 4
8~&, i (2H@brs) e 5.3~5.
8 (3H@s) * 6.1=7.8 (13H,
arrogant), 9.16 (II-I, d, J-7H).

9.24 (lH, d, J■7Hz) UV λ" OHm5 (#) 寞20g (12XlG
'), 272 (4,7111 XIO"), 295 (5,3X10") Ferric chloride color reaction: Positive (dark green) -3,4-dihydroxybenzamide 5,
Using N-cyanomethyl-3,4-dihydroxybenzamide z7f instead of Of, and using 5.8P of trimethylsilyl chloride and 5.22P of -43-
(3,4-Dihi)"Rxybenzoyl)-3-cyanomethyl-1-ureido 1-α-phenylacetamide] Benicran 1! (hereinafter also referred to as compound ①) is obtained as a white powder.

I R' Ill@s (3) ” 3700~2
300-1770-1700.1600.1515 N M B (DM80-d@, 60MHx) J (
Fpl) = 1.41 (3H.

s) , 1.56 (3H, s) , 4.20 (IH, @
), 4g (2H-bri) e 5.3-5.8 (3
)T-vm)-&8~7.6(8H9淋),
9.21 (2H, d,, J-7H Tom) UVλ14;
; ms(g): 207 (3,3X l O')
, 22g(J[s *278(tOXlo”), 29
6(7,4X'-103) ferric chloride color reaction: positive (
(dark green) (h) Example 1 In (1), N-(3-hydroxypropyl)-3,4-dihydroxybenzamide LOP
KN-furfuryl-kame 4-dihydro in place of O ■Xypenzuado 5. By using Of and 9.2f% trimethylsilyl chloride and triethyl acene [2F and following the same treatment, 6-(D (-)-α-(3-(
3,4-dihydroxybenzoyl)-3-furfuryl-
1-ureido)-g-phenylacetoand]penicillane (hereinafter also referred to as compound J) 5.5 f is obtained as a white powder.

r RII"'(cgi")! 3700-2200
．． 1770.

1@-1 1680,1600,151O NMR (DM80-4.60MHz) J(P): L
41 (3H, s).

1.55 (3H, s), 420 (IH, s), 48
~5.1 (2H, brs), 5.3~5J (3H
, s), &1~7.6(11H,s), 9.18(
2H, d, J-7Hg) U V2”0Hss (#):
20g (3,4X10'), 272 (5,3鵠・-XIO"), 294 (5,8X1G") Ferric chloride color reaction: Positive (dark green) (S) In Example 1 (1) N-(3-hydroxypropyl)-3,4-dihydroxybenzamide 5,O
CKN-(3-acetoxypropyl)-3,4 instead of f
-dihydroxybenzamide5. Of and trimethylsilyl chloride &lf, )! Using ethyl amine 7.22 and treating in the same manner, 6~(D (
-)-α-(3-(4-dihydroxybenzoyl)-
3-(3-acetoxypropyl)-1-ureido)-a
-7 enylacetamide] penicillane beak (hereinafter also referred to as compound) 15f is obtained as a white powder.

I Ry"'(m-')! 3700~!300.
1775.

Number 1 1730.168G, 1600.1510°N M R
(DM80-d@, 60MHx) J(P): L41(
3H, m).

L5-11 (2H, br), 1.55 (3H, s)
, LSI (3H=s)'t3.6~41 (4)1.
m) -4,21 (IH.

s) #5.3~5.8 (3He @I) s
5L8-7.6 (8H, gm).

'117 (IH, d, J-7H earthquake), 9.30 (IH
,d.

J-7H Fuji) UVλ pull OH, -(S1205 (10' to 2,8)
, 223 (71+1).

Sacrifice 51 272 (tOXlo"), 293 (4,4X10") Ferric chloride color reaction: Positive (dark green) Example 1 (1) N-(2-hydroxyethyl)-kame 4-dihydro oxibenz And5. Of and trimethylsilyl chloride 13.8F were suspended in a mixed solvent of 30ml of dry dichloromethane and tetrahydro-75, and a dry dichloromethane solution 3 containing 12.3f of triethylamine was added.
0d is added dropwise under ice-water cooling. Warm liquid in nitrogen atmosphere 4
Heat to reflux for 0 minutes.

Then, under cooling, at -10 to -5°C, tritalolomethyl chloroforme)3. Drop Od. After gradually raising the liquid temperature and stirring at 0 to 5°C for 2 hours, one drop of phosgene and the solvent were distilled off under reduced pressure. 80 d of dry dichloromethane is added to the residue, insoluble matter is removed by natural filtration, and the residue is subjected to the reaction described below.

(2) Anhydrous arepicillin 116! Trimethylsilyl chloride &4F is added dropwise to 110mj of a dry dichloromethane solution containing F and 7.6t of triethylamine at 5 to 10°C. After stirring at the same temperature for 1 hour, a dichloromethane solution prepared in Queen (1) was added dropwise at 0 to 5° C. while stirring. 5
After stirring at ~10°C for 1 hour, add cold saturated saline solution to approx.
The organic layer is separated. Cough organic layer with cold saturated saline solution for 30 minutes
The aqueous layer was washed with 100 d of ethyl acetate, and the aqueous layer was washed with 100 d of ethyl acetate.
- is added, the μ value is adjusted to about L5 with cold 6N hydrochloric acid, and after adding salt to - to saturate the aqueous layer, the organic layer is separated. #
The organic layer was washed with 100 d of cold saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was washed with 8ephadex L H-20 (FINE OH
(trade name of dextran crosslinked polymer manufactured by RMIOAL8)
The s-CD was subjected to column chromatography, eluted with acetone, concentrated under reduced pressure until the liquid volume was about 30 dK, and treated with diethyl ether 30G-.
(-)-α-[3-(, 4-dihydroxybenzoyl)-3-(2-hydroxyethyl)-1-ureido)-
[alpha]-phenylacedo]penicillanic acid (hereinafter also referred to as compound B) 109 is obtained as a white powder.

I R&”'(ai)t3700~2200.1
770° -- 1675, 1600, 151O NMR (DM80-4.60MHz) J (flpm
): 1.41 (3H.

s), L56 (3H, s), 13-4.1 (4H, s)
.

411 (IH, s), 5.3-5.8 (3H, s)
, 6.7-7.6 (8H, s), 9.21 (IH, d
, J-7Hz).

9.33 (IH, d, J-7Hz) UV λ”
0)Ism(#)! 204 (3,3X10'), 221
(ag shoulder) jt6 (51,4X1G"), 295 (5,6X
10") Ferric chloride color reaction: Positive (dark green) Example 1 To a solution of 12.9f of amoxicillin trihydrate in 70d and 111ml of dry dichloromethane was added 119f of N,0-bis(trimethylsilyl)acetamide at 10 to 15°C. was added and stirred until it became homogeneous, and to this was added dropwise the 9-dichloromethane solution prepared in Example 1 (1) at 5 to 10°C. At the same temperature, 1
After stirring for an hour and evaporating to dryness at room temperature under reduced pressure, 250d of ethyl acetate and 50111j of tetrahydrofuran were added to the residue.
A mixed solution of cold IN-tJIF1100d is added, and the organic layer is separated. The organic layer is washed with 300 d of cold saturated brine, and then the target product is extracted in two portions with 300 d of cold aqueous sodium bicarbonate solution. Add 25 ethyl acetate to this
Add a mixed solvent of 0d and Tetrahydro7ran 5011j, adjust the value to about L5 with cold 6N hydrochloric acid, and then add common salt to saturate the aqueous layer. After washing with 100 d of cold saturated brine, it is dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue is subjected to column chromatography on activated carbon (for lithography) and eluted with acetone. The eluate was collected and concentrated under reduced pressure until the liquid volume was about 30 d, and then dissolved in 300 d of Kl? in ethyl ether. When added under stirring, 6-CD (-)-α-C3-(turtle 4-dihydroxybenzoyl)-3-(3-hydroxypropyl)-1
45
f is obtained as a white powder.

I RyKB'(j"53700~2300.177
0゜鵠1- 1680.1610.1515 NM & (DM80-4g, 60MHs) J(PI
) :L42(3H,s).

15g (3H, s), 1.3-1.9 (2H, br),
11-4.0 (4H, s), 4.20 (IH, m)
, 5.3-5.7 (38,s) , 6.5-7.3
(7H, s), 9.0 (2H.

br) UVλ"OHm5(#)t206(18XlO'), 2
24 (12 sacrifices - XIO'), 276 (&6X10"), 283 (6,4
X1♂), 295 (5,4X10) Ferric chloride color reaction: Positive (dark green) Example Table (1) D (-) - Dry dichloromethane containing 4.72 of phenylglycine and 7.82 of trimethylsilyl chloride To the suspension of 100d, triethylamine 7°1f was added dropwise at 5 to 10°C. N,O-bis(trimethylsilyl)acetamide 1wII was then added dropwise at the same temperature, and after stirring for 1 hour at room temperature, Example 1 The dichloromethane solution prepared in (1) is added dropwise at 5 to 10° C. while stirring. The mixture was stirred at the same temperature for 1 hour, then evaporated to dryness at room temperature under reduced pressure, and the residue was mixed with 6M ethyl 3G0. A mixture of llj and cold 6N hydrochloric acid lowLl is added, and the organic layer is separated. After washing the mosquito organic layer with 300 d of cold saturated saline,
Extract the target product in two portions with 300 d of cold anastomated aqueous sodium bicarbonate solution.Then, add 250 ml of ethyl acetate to the aqueous layer.
d and adjust the concentration to about 1.5 with cold 6N hydrochloric acid, add common salt to saturate the aqueous layer, and separate the organic layer.

The separated organic layer was washed with cold saturated saline LOO*#, dried over anhydrous magnesium sulfate, and diluted with solvent t~ under reduced pressure. To leave. The residue was crystallized from a7tone-chloroform,
When recrystallization is performed in the same solvent system, D(-)3-(-α-W<-dihydroxybenzoyl)-3-(3-hydroxypropyl)-1-ureido)phenylacetic acid5.
59 was obtained as white crystals.

Melting point 139-141℃ (decomposition) Elemental analysis onI (ON, 伽・HIO 0
HN Calculated value -5 & 16 5.46 & 89 Actual value (2)
5430 5.40 [87I 8 ν (
Country ): 3540.3500.1690゜gI&aII
1 1170.1595.152O N M B (DM80-11.60MHg) δ(p)
=1.3~10 (2H.

S) i35 (2M, t, J-6H1), 3.73 (2
H.

t, J-&5Hz) s5.22 (IHed, Jm7
Hz).

6.7-7.5 (8H, s), 9.19 (IH, d, J
-7Hg) Ferric chloride color reaction: Positive (dark green) (2) Add 5 to 10°C to the dried DikQk meta y50+jlDII suspension containing phenylacetic acid LO2 and 4.9f of trimethylsilyl chloride obtained in (1) above. After adding 4.2 t of triethylamine dropwise, the mixture was stirred at 15 to 20°C for 1 hour to obtain a trimethylsilylated solution of the above-mentioned 7 EL acetate, which was then subjected to the reaction described below.

(3) Dry dichloromethane solution containing 1.2 F (80 dK), at -20°C, add 0.8 f of dimethylformamide, stir at 0 to 5°C for 1 hour, and then stir at -30°C to prepare the above ( 2) and stirred for L5 hours at °C. Then, to this was added 50 d of dry dichloromethane containing 2.92% of 6-amitubenicilanic acid (D!%! cloudy liquid KN,
A solution in which 5.5 f of O-bistrimethylsilylacetamide was added and dissolved was poured down at -10 to -15°C, and stirred at the same temperature for 1 hour.

Hereinafter, the same extraction operation and purification as in Example 1 (2) were performed to obtain compound 4. Get the Of tube. This product was identical to that obtained by the method of Example 1 in IR, NMR and UV.

(B) Example 4 In (1), KN-(2-hydroxyethyl)-4-dihydroxybenzamide was used instead of N-(3-hydroxypropyl)-4-dihydroxybenzamide, and the same treatment was carried out. ,D(
-)-α-(3-(3,4-dihydroxybenzoyl)
Compound B is obtained by synthesizing -3-(2-hydroxyethyl)-1-freido-1 phenyl acetic acid and subjecting it to the same operation as in Example 4(2). This product was identical to that obtained by the method of Example 2 in IR, NMR and UV.

(b) 1! In Example 4 (1), dibenzamide in KN-(5-hydroxypentyl)-&44-dihydro was used instead of N-(3-hydroxypropyl)-λ44-dihydroxypenzagide, and the same treatment was carried out, and D (
-)-α-(3-(3,4-dihydroxybenzoyl)
-3-(5- and cyclocypentyl)-1-ureido)phenylacetic acid is synthesized and subjected to the same operation as in Example 4(2) to obtain Compound 0. This product was obtained by the method of Example 1 (a) and was IR.

Consistent in NMR and UV.

(c) II! In Example 4(1), instead of dibenzamide in N-(3-hydroxypropyl)-3,4-dihydro, ? The same treatment was performed using dibenzamide in KN-(2-(2-hydroxyethoxy)ethyl)-34-dihydro to give D(-)-a-(3-(3,4-dihydroxybenzoyl)-3- (2-(2-Hydroxyethoxy)ethyl)-1-ureido]phenylacetic acid is synthesized and the same procedure as in Example 4(2) is carried out to obtain the compound R. 1 (b), and the IR, NMR, and UV values were identical to those obtained by method 1 (b).

(d) In Example 4 (1), DK instead of N-(3-hydroxypropyl)-kame 4-dihydroxypenzuad
Using N-(2-methoxyethyl)-λ4-dihydroxypendazole and reducing the amounts of trimethylsilyl chloride and triethylamine by 1 molar equivalent, the same treatment was carried out to obtain D(-)-α- (3-(turtle 4
Compound 8 is obtained by synthesizing -dihydro-xybenzoyl)-3-(2-methoxyethyl)-1-ureido)phenylacetic acid and conducting the same procedure as in Example 4 (2). This product was identical to that obtained by the method of Example 1 (c) in IR, N)IJII and UV.

(E) In Example 4 (1), N-(2-cyanoethyl)-3,4-dihydroxybenzand was used instead of N-(3-hydroxypropyl-&4-dihydroxybenzamide), and trimethylsilyl The amount of diluted chloride and triethylamine was reduced by 1 molar equivalent, and the same treatment was carried out to obtain D(-)-α-(3-(turtle 4-dihydroxybenzoyl)-3-(2-cyanoethyl)-1). -Ureido)phenylacetic acid is synthesized and the compound ? is obtained by performing the same operation as in Example 4 (2). This compound is the same as that obtained by the method of Example 1 (d).几, NMR and UVK1? were consistent.

(f) In Example 4 (1), N-(3-hydroxy 7
N-ethoxycarbonylmethyl-4-dihydroxybenzand was used instead of enyl)-4-dihydroxybenzand, and the amounts of trimethylsilyl chloride and triethylamine were reduced by 1 molar equivalent, and the following Perform the same process and D(-)-α-(3-(3
, 4-dihydro-4-xybencyA-)-3-ethyacical is synthesized with nylmethyl-1-')-phenylacetic acid, and this turtle is subjected to the same operation as in Example 4 (2).
Compound G is obtained. This is the same IR as No. 4 obtained by the method of Example 1 (e).

Consistent in NMR and UV.

(g) In Example 4 (1), N-benzyl-3,4-dihydroxybenzand was used instead of N-(3-hydroxypropyl)-kame-4-dihydroxybenzamide, and the amounts of trimethylsilyl chloride and triethylamine were changed. The amount was reduced by 1 molar equivalent and used, followed by the same treatment to obtain D(=)-α-(3-(Otori-4-dihydroxypensoyl)-3-benzyl-1-ure(do)7-ethyl acetate) Compound H is obtained by synthesizing this compound and subjecting it to the same operations as in Example 4 (2).

This product was obtained by the method of Example 1 (f) and was round and I
Consistent in R, NMR and UN/.

(H) In Example 4 (1), N-(3-hydroxypropyl)-3,4-dihydroxybenzand 111
Using 9KN-cyanomethyl-kame 4-dihydroxybenzamide instead of \ and reducing the amounts of trimethylsilyl chloride and triethylamine by 1 molar equivalent, the same treatment was carried out to obtain D (-)-α-(3- (3
, 4-dibenzoyl in dihydro)-3-wakai≧cyanoethyl imaichi 1-? When L/ido J7 ether acetic acid was synthesized and the same procedure as in Example 4 (2) was performed, the compound! get. This 4 corresponds to that obtained by the method of Example 1 (g) in IR, NMR, and UV.

(S) DK instead of N-(3-hydroxypropyl)-&4-dihydroxybenzamide in Example 4 (1)
The same treatment was carried out using N-furturyl-silicone in 4-dihydro and the amounts of trimethylsilyl chloride and triethylamine were reduced by 1 molar equivalent, and D(-)-1-(3-(! Compound J is obtained by synthesizing L4-dihydroxybenzoyl-3-furfuryl-1-ureido)phenylacetic acid and subjecting it to the same operations as in Example 4(2).

This is the same as the book obtained by the method of Example 1 (H).
Consistent in R, NMR and UV.

(N) In Example 4 (1), N-(3-acetoxypropyl)-&4-dihydroxybenzamide was used instead of N-(3-hydroxypropyl)-4-dihydroxybenzamide, and trimethylsilyl chloride and triethylamine were used. The amount of is reduced by 1 molar equivalent, and the same process is performed to obtain D (-) -t
(3-(mi-4-dihydroxybenzoyl)-3-(3-
Compound Kt was obtained by synthesizing (acetoxypropyl)-1-ureido 3-phenylacetic acid and performing the same operation as in Example 4 (2)), Kononoke Example 1 (S)
The book and IR obtained by the method.

Consistent in NMR and UV.

(l) In Example 4 (1), KD(-)-(4-hydroxy7enyl)glycine was used instead of D(-)-phenylglycine, and the following f5]IIIK treatment was performed to give D(-)
-α-13-(Toki 4-dihydro 4-dibenzoyl) -3
,-(3- and Doro Life Shibu μ Pill)-! −Ureido)−α
-(4- and diphenyl)acetic acid is synthesized, and this product is subjected to the same operation as in Example 4 (2) to obtain a compound from K. This IR was obtained by the method of Example 3.

Consistent in NMR and UV.

Example 5゜(1) N-(3- and Dota xypropyl)-Kame4-di4f
and then add triethyl isoIL while stirring at room temperature.
Slowly add a small drop of 98F. The mixture was heated under reflux for 60 minutes, then cooled to 10°C, trichloromethylchloroformate (16d) was added, and the mixture was stirred at 21°C for 3 hours.

(2) 9.5f of anhydrous ampicillin was added to 100% of ethyl acetate.
After making the medium KJI cloudy and adding trimethylsilyl chloride &5f, add triethyl iso[1] while stirring under water cooling.
Drip f. After stirring for 1 hour at 5-10°C, add the tetrahydrofuran solution prepared in (1) and add about 2
After the reaction, which is stirred at 0° C. for 1 to 2 hours, 200 d of water is added and further stirred.

After light stirring, the mixture is allowed to stand and the organic layer is separated. The organic layer is washed with cold saturated brine, and then extracted with 200 d of cold saturated aqueous sodium bicarbonate solution. The aqueous layer, which has been stirred for 0 minutes, is washed with ethyl acetate. After adjusting the value to about 1-2 with hydrochloric acid and further adding common salt to saturate the aqueous layer, the organic layer is separated. The organic layer was washed three times with 100 d of cold saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and then washed with
When added under stirring to 500 d of hexane, the crude compound 1
1.5f is obtained as a yellow-white powder.

This crude compound &7. Of and sodium bicarbonate α
Dissolve 9f in cold 7 to 30d, then dial in HP
-30 (trade name, manufactured by Mitsubishi Kasei Corporation) and subjected to column chromatography (350 m#), and eluted with water and then aqueous acetone (acetone concentration: 1O'A%). Add 200 d of ethyl acetate to the collected eluate, bring the value to about 1.5 with cold 6N hydrochloric acid, then add common salt to saturate the aqueous layer, and then separate the organic layer. The obtained organic layer is washed with cold saturated saline solution 100+wj, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure until the liquid volume becomes about 30 dK. When this is added to 300 d of duck-hexane under stirring, the compound mulof is obtained as a white powder. This product was obtained by the method of Example 1 and IR, NMI and UV
It was agreed that

(B) Example 5 In (1), N-(2-hydroxyethyl)-kame-4-dihydroxybenzamide was used instead of N-(3-hydroxypropyl)-3,4-dihydroxybenzamide, and the same applies hereafter. Compound B is obtained. This book was identical to that obtained by the method of Example 2 in IR, NMR and OV.

(0) Amoxicillin trihydrate 12.9 N, O-bis(
Add 119 ft of trimethylsilyl)acetamide and stir until homogeneous. To this, add the tetrahydro 7 run solution prepared in Example 4 (1) and stir at about 20°C for 1-2 hours. Thereafter, the same treatment is performed to obtain compound L 4.7 f. The material obtained by the method of this turtle welfare example 3 and IR,
Consistent in NMR and UV.

Applicant: Chugai Pharmaceutical Co., Ltd. Continuation of page 1 0 shots by Takao Noto 3-41-8 Takada, Toshima-ku, Tokyo 3-41-8 Takada, Toshima-ku, Tokyo Inside Chugai Pharmaceutical Co., Ltd. 0 shots clear person Yusuke Harada ′ 3-41-8 Takada, Toshima-ku, Tokyo Inside Chugai Pharmaceutical Co., Ltd. 0 shots clear by Hisao Endo 3-41-8 Takada, Toshima-ku, Tokyo Inside Chugai Pharmaceutical Co., Ltd. 0 shots clear person Takao Kimura 3-41-8 Takada, Toshima-ku, Tokyo Inside Chugai Pharmaceutical Co., Ltd. 0 shots clear person Kana Kojima 3-41-8 Takada, Toshima-ku, Tokyo 3-41-8 Takada, Toshima-ku, Tokyo Inside Chugai Pharmaceutical Co., Ltd. 0 shots by Hiroshi Okazaki 3-41-8 Takada, Toshima-ku, Tokyo ・Within Chuugai Pharmaceutical Co., Ltd. 0 shots: Haruki Ogawa 3-41-8 Takada, Toshima-ku, Tokyo Inside Chugai Pharmaceutical Co., Ltd. 0 shots clear person Minoru Shindo 3-41-8 Takada, Toshima-ku, Tokyo Inside Chugai Pharmaceutical Co., Ltd.

Claims (1)

[Scope of Claims] 1) The following general formula (in the formula, R1 is a hydrogen atom and a hydroxyl group,
A lower alkyl group of 01-4, a lower alkanoyl group of 01-4, a hydroxyl group or a lower alkyl group of 90-4 substituted with a hydroxyl group or a lower alkoxy group of 01-4, is a hydrogen atom, and 9 is O1-4 is a lower alkyl group, ``is a hydrogen atom, a nitro group, or a lower alkoxy group of O1 to 4, R'' is a hydroxyl group or a group -000R'' (``is the same as above), and 饅 is a group in which Y is a group ÷ When it is ofs, 2t-1 and when it is other groups, use l. Tsuru means 1, 2 maso means 3, 1 means 0, 1.2t means 3. ) is a compound represented by the general formula (wherein, Bl means a hydroxyl group and yl is a group corresponding to the above YK, and a hydroxyl group is When a carboxyl group exists, it means that it (etc.) is protected. z#i^ means a four-gen atom. (In the formula, m''/d glacial hydrogen atom. The acid group means a preserved hydroxyl group, and l means a hydrogen atom.) 1. A production process characterized in that the compound is reacted with a reactive derivative thereof and then the protective groups, if present in the product, are removed.