JPS6111958B2 - - Google Patents

Description

[Detailed description of the invention]

The method of the invention applies to a class of antibacterial agents commonly referred to as semi-synthetic penicillins, preferably those characterized by an alpha-amino group on the 6-position acyl side chain, such as ampicillin and amoxicillin. This invention relates to a new intermediate used in a new manufacturing method and a manufacturing method thereof. The first commercial penicillin with an α-amino group on the 6-acylamino side chain was 6-(D-α-amino-α-phenylacetamido)penicillanic acid or ampicillin (U.S. Pat.
(See No. 2985648). Amoxicillin is also an antibacterial agent used in human therapy and is commercially available as the trihydrate of the free acid (i.e., zwitterion). However, the lever is, for example, British Patent No. 978178 J.Chem.Soc.
(London), pp. 1920-1922, 1971; Fungicides and Chemotherapy - 1970, pp. 407-430 (1971). Its chemical name is 6-[D-α-amino-α-(p-hydroxyphenyl)acetamido]penicillanic acid. The use of amino acid chloride hydrochloride to make the above penicillins has been demonstrated in patent documents such as British Patent No. 938321 and British Patent No. 959853 under anhydrous conditions.
(the latter being disclosed in British Patent No.
1008468 and U.S. Pat. No. 3,249,622 (utilizing protection by the silyl group during acylation of the carboxyl group of 6-aminopenicillanic acid), and in cold aqueous acetone as disclosed in British Patent No.
It is disclosed in No. 962779. These penicillins are amphoteric amino acids, so their isolation involves certain aliphatic asymmetric side chains (as disclosed, for example, in U.S. Pat. No. 3,157,640, U.S. Pat. No. 3,271,389). amines (often referred to as liquid amine resins), which have previously been used to isolate the amphoteric amino acid 6-aminopenicillanic acid (see US Pat. No. 3,008,956). Improved methods for isolating and purifying these penicillins are described, for example, in U.S. Pat. No. 3,180,862 using β-naphthalene sulfonate, and in British Patent No. 3,198,804, which involves isolation of intermediates and easy hydrolysis of hetacillin. It is revealed in the issue. The use of silyl groups for protection of the carboxyl groups of natural penicillins during chemical cleavage to 6-aminopenicillanic acid is disclosed in US Pat. No. 3,499,909. The use of silylated 6-aminopenicillanic acid during anhydrous acylation with amino acid chloride hydrochloride has been reported in numerous patents such as U.S. Pat.
3479018, U.S. Patent No. 3595855, U.S. Patent No.
3654266, U.S. Patent No. 3479338, U.S. Patent No.
This is disclosed in No. 3487073. Some of these patents also disclose the use of liquid amine resins. U.S. Patent No. 3912719, No. 3980637, No.
See also issue 4128547. British Patent No. 1339605 discloses a silylated derivative of 6-aminopenicillanic acid and a reactive derivative of D-(-)-α-amino-p-hydroxyphenylacetic acid with a protected amino group (chloride hydrochloride). various specific details of the preparation of amoxicillin by reacting the silyl group with the silyl group (containing ), followed by removal of the silyl group by hydrolysis or alcoholysis, and subsequent recovery of the amoxicillin, usually as a crystalline trihydrate, if possible. Contains examples. Thus, in Example 1, crystalline amoxicillin was obtained from an aqueous solution by isoelectric precipitation at, for example, pH 4.7. Perhaps in this example, the crude product (before isoelectric precipitation)
Water with an acidic pH like 1.0 (e.g. hydrochloric acid solution)
〓〓〓〓〓
Purification was carried out by dissolving in the presence of a water-immiscible organic solvent such as methyl isobutyl ketone (4-methylpentan-2-one). The same procedure was used in US Pat. No. 3,674,776. The following structural formula (However, B is a trialkylsilyl group)
in an anhydrous inert organic solvent, preferably in methylene chloride, in the presence of a weak base, preferably propylene oxide, preferably at a temperature above -10°C, more preferably in the range -8 to 20°C. and more preferably in the range of 0 to 20°C, most preferably at about 20°C, with about an equivalent amount of acid chloride or chloride hydrochloride (preferably the latter is added in portions to the solution of the former). , and then, if desired, a conventional process for the production of penicillin, consisting of converting the B group to hydrogen, is provided by the present invention. The conventional penicillins defined herein are those already described in patents or literature (including abstracts thereof). Also according to the invention, dry carbon dioxide as the gas can be used with the formula (However, B is a trialkylsilyl group)
in an anhydrous inert organic solvent, preferably methylene chloride, at room temperature or from 0°C to 100°C.
The formula consists of adding until the reaction is complete at a temperature in the range of (where B is the same as above) is provided. formula in the presence of a weak base, preferably propylene oxide, in an anhydrous inert organic solvent, preferably methylene chloride, preferably -
10°C or higher, more preferably in the range of -8°C to 20°C,
More preferably at a temperature in the range 0°C to 20°C, most preferably about 20°C, about equimolar amounts of D-(-)-α-
aminoaryacetyl chloride hydrochloride, preferably D-(-)-2-phenylglycyl chloride hydrochloride or D-(-)-2-p-hydroxyphenylglycyl chloride hydrochloride (the latter is preferably added in portions to a solution of the former) as a preferred embodiment of the present invention, preferably ampicillin or amoxicillin. One of the surprising features of this new method is the stability of the anhydrous acylation solution. This can be maintained for long periods of time even at room temperature without appreciable decomposition of the penicillin molecule. This is in contrast to the behavior of the acylation solution in previously described methods. The advantage of this stability is that
Usually below 0°C, much higher than the temperature normally used for ampicillin production, which is typically about -10°C.
The elevated temperature (we used room temperature) allows the acylation reaction to be carried out. Dry as a gas, consisting of adding carbon dioxide to a solution of trimethylsilyl 6-trimethylsilylaminopenicillanate in an anhydrous inert organic solvent, preferably methylene chloride, at room temperature or in the range from 0 to 100 °C until the reaction is complete. The following formula Also provided as a preferred embodiment is a method for making the compound. formula (However, B is a trialkylsilyl group)
Also provided as embodiments of the invention are compounds having . Furthermore, the following formula Compounds having the following are provided as preferred embodiments. This compound is a bissilylated carbamate of 6-APA, SCA, 6-trimethylsilyloxycarbonylpenicillanic acid TMS ester,
It goes by various names such as TMSO ₂ C, APA, and TMS. Given the well-known fact that the reaction of 6-APA with carbon dioxide destroys 6-APA and produces 8-hydroxypenicillanic acid, as disclosed for example in U.S. Pat. No. 3,225,033. The existence of the above compound is surprising. The key to quantitatively obtaining 6-trimethylsilyloxycarbonylaminopenicillanic acid trimethylsilyl ester (TMSO ₂ C·APA·TMS) is first of all to completely synthesize the 6-APA bisTMS precursor. This is achieved by reacting 6-APA with hexamethyldisilazane (HMDS) as shown in the following schematic outline.

【table】

【table】

The completion of the bistrimethylsilylation reaction was determined by NMR
can be easily tracked using The 3-trimethylsilyloxycarbonyl group shows a methylsilyl single line at 0.31 ppm (tetramethylsilane = 0), while the 6-trimethylsilylamine group shows a methyl silyl line at 0.09 ppm.
Showing a luciryl single line. The 6-APA trimethylsilylation reaction has hitherto been carried out only in methylene chloride. but,
Other solvents such as acetonitrile, dimethylformamide, or even HMDS itself can be used. Conversion of trimethylsilylamino groups to trimethylsilyloxycarbonylamino groups is easily accomplished by bubbling dry CO ₂ into the reaction solution. The conversion can be easily followed as the trimethylsilylamino singlet at 0.09 ppm fades as a new singlet of the trimethylsilyloxycarbonylamino group appears at 0.27 ppm. When this method is used to produce ampicillin, ampicillin anhydride, ampicillin trihydrate, amoxicillin, amoxicillin trihydrate, U.S. Pat.
3912719, 3980637, 4128547 and other patents and publications cited therein, the final product can be isolated, Refined. The acid chlorides used in the following examples can be replaced with various other acid chlorides to produce conventional penicillins. Thus, the acid chloride may be selected to introduce any desired acyl group at the 6-amino position, as is known in the art, eg, US Pat. No. 3,741,959. Thus, certain acyl groups can be introduced including, but not limited to, those specified in the general formula below. (i) R ^u C _o H _2o CO- where R ^u is aryl (carboxylic or heterocyclic), cycloalkyl, substituted aryl,
It is a substituted cycloalkyl, or a non-aromatic or mesoionic heterocyclic group, and n is an integer of 1-4. Examples of this group are phenylacetyl, substituted phenylacetyl, such as fluorophenylacetyl, nitrophenylacetyl, aminophenylacetyl, acetoxyphenylacetyl, methoxyphenylacetyl, methylphenylacetyl, or hydroxyphenylacetyl. ; N,N-bis(2-chloroethyl)aminophenylpropionyl; thiene-3-acetyl; 4-isoxazolyl and substituted 4-isoxazolyl acetyl; pyridylacetyl; including tetrazolylacetyl or sydononeacetyl groups . A substituted 4-isoxazolyl group may be a 3-aryl-5-methylisoxazol-4-yl group, where aryl is, for example, phenyl or halophenyl, such as chlorophenyl or bromophenyl. An acyl group of this type is 3-O-chlorophenyl-5-methylisoxazol-4-yl-acetyl. (ii) C _o H _2o+1 CO− where n is an integer from 1 to 7. Alkyl groups may be straight-chain or branched and may be substituted, if desired, via oxygen or sulfur atoms or, for example, by cyano groups. Examples of such groups include cyanoacetyl, hexanoyl, heptanoyl, octanoyl and butylthioacetyl. (iii) C _o H _2o-1 CO- where n is an integer from 2 to 7. This group may be straight-chain or branched and may contain intervening oxygen or sulfur atoms if desired. An example of such a group is allylthioacetyl. However, R ^u has the meaning defined in (i) and may also be benzyl, and R ^v and R ^w may be the same or different, and are hydrogen, phenyl, benzyl,
It may also be phenethyl or lower alkyl.
Examples of such groups are phenoxyacetyl, 2-phenoxy-2-phenylacetyl, 2-phenoxypropionyl, 2-phenoxybutyryl, benzyloxycarbonyl, 2-methyl-2-phenoxy Includes propionyl, p-cresoxyacetyl and p-methylthiophenoxyacetyl. However, R ^u has the meaning as defined in (i) and may also be benzyl, and R ^v and R ^w have the meaning as defined in (iv). Examples of such groups are S-phenylthioacetyl, S-chlorophenylthioacetyl, S-fluorophenylthioacetyl, and
Includes lysylthioacetyl, and S-benzylthioacetyl. (vi) R ^u Z(CH ₂ ) _n CO− where R ^u has the meaning defined in (i) and may also be benzyl, Z is oxygen or a sulfur atom, and m is 2 to It is an integer of 5. An example of such a group is S-benzylthiopropionyl. (vii) R ^u CO- where R ^u has the meaning defined in (i). Examples of such groups are benzoyl, substituted benzoyl (e.g. aminobenzoyl), 4-isoxazolyl and substituted 4-isoxazolylcarbonyl, cyclopentanecarbonyl, sidonecarbonyl, naphthoyl and substituted naphthoyl (e.g. 2-ethoxynaphthoyl) quino Zarinylcarbonyl and substituted quinozalinylcarbonyl (e.g. 3-carboxy-
2-quinozalinylcarbonyl). Other possible substituents for benzoyl are alkyl, alkoxy, phenyl or carboxy, alkylamido, cycloalkylamide, allylamide,
phenyl substituted with (lower)-alkylamide, morpholinocarbonyl, pyrrodilinocarbonyl, piperidinocarbonyl, tetrahydropyrrolidino, furfurylamide or N-alkyl-N-anilino, or derivatives thereof; Such substituents include 2- or 2- and 6-
It may be a rank. Examples of such substituted benzoyl groups are 2,6-dimethoxybenzoyl, 2-biphenylcarbonyl, 2-methylamidobenzoyl and 2-carboxybenzoyl. When the R ^u group represents a substituted 4-isoxazoyl group, the substituents may be as described above under (i). Examples of such 4-isoxazole groups are 3
-phenyl-5-methyl-isoxazole-4
-ylcarbonyl, 3-O-chlorophenyl-5
-methyl-isoxazol-4-ylcarbonyl and 3-(2,6-dichlorophenyl)-5-methylisoxazol-4-ylcarbonyl. However, R ^u has the meaning defined in (i), and X is amino, substituted amino (e.g. acylamide or 7
- groups obtained by reacting side chain amino groups and/or groups with aldehydes or ketones, such as acetone, methyl ethyl ketone or ethyl acetoacetate), hydroxy, carboxy, esterified carboxy, triazolyl, tetrazolyl, cyano, halogeno, acyloxy (eg formyloxy or lower alkanoyloxy) or an etherified hydroxy group. Examples of such acyl groups are α-aminophenyl acetyl, α-carboxyphenylacetyl and 2,2
-dimethyl-5-oxo-4-phenyl-1-imidazolidinyl. However, R ^x , R ^y and R _z may be the same or different and each represents lower alkyl, phenyl or substituted phenyl. An example of such an acyl group is triphenylcarbonyl. However, R ^u has the meaning defined in (i) and may also be hydrogen, lower alkyl or halogen-substituted lower alkyl, and Y represents oxygen or sulfur. An example of such a group is Cl( _CH2 ) _2NHCO . However, X has the meaning defined in (viii), and n is 1 to
It is an integer of 4. Examples of such acyl groups are 1-
Amino-cyclohexanecarbonyl. 〓 Aminoacyl, for example R ^w CH (NH ₂ ).
(CH ₂ ) _o CO- (where n is an integer from 1 to 10)
or NH ₂ C _o H _2o A _r (CH ₂ ) _n CO− (where m is 0
or an integer from 1 to 10, n is 0, 1 or 2, R ^w is a hydrogen atom or an alkyl, aralkyl or carboxyl group or a group as defined above for R ^u , and A _r is Arylene group, e.g.〓〓〓〓〓
For example p-phenylene or 1,4-naphthalene. ) Examples of such groups are disclosed in GB 1054806. A group of this type is the p-aminophenyl acetyl group. Other acyl groups of this type are δ-aminoadipoyl and its derivatives derived from naturally occurring amino acids, such as N-benzoyl-δ-
Includes aminoadipoyl. 〓 Substituted glyoxylyl group of ^{the formula R y .} CO . , substituents are, for example, one or more halogen atoms (F, Cl, Br or I), methoxy, methyl or amino groups, or fused benzene rings. When the acyl group to be introduced contains an amino group,
It may be necessary to protect it during various reaction steps. Conveniently, the protecting group is one that can be removed by hydrolysis without affecting the remainder of the molecule, especially the lactam and 7-amide bonds. The amine protecting group and the esterification group at the 4-COOH position can be removed using the same reagent. An advantageous operation is to remove both at the final stage of the process. Protected amino groups include urethane, arylmethyl (eg trityl)amino, arylmethyleneamino, sulfenylamino or enamine types. Enamine blocking groups are particularly useful in the case of O-amino-methylphenylacetic acid. Such groups generally include dilute mineral acids such as dilute hydrochloric acid, concentrated organic acids such as concentrated acetic acid, trifluoroacetic acid and cryogenic acids such as -
It can be removed using one or more reagents selected from liquid hydrogen bromide at 80°C. A convenient protecting group is the t-butoxycarbonyl group, which is protected with a dilute mineral acid, such as dilute hydrochloric acid, or preferably with a strong organic acid, such as formic acid or trifluoroacetic acid, for example at a temperature of 0 to 40°C, preferably Room temperature (15-25
It is easily removed by hydrolysis at temperatures (°C). Another convenient protecting group is the 2,2,2-trichloroethoxycarbonyl group, which can be cleaved with reagents such as zinc/acetic acid, zinc/formic acid, zinc/lower alcohol or zinc/pyridine. The NH ₂ group can be protected as NH ₃ ⁺ by using amino acid chlorides as acid addition salts under conditions where the amino group remains protonated. The acid used to form the acid addition salt is preferably one having a pka (in water at 25°C) of X+1, where X is the carboxyl group of the amino acid.
pka value (in water at 25°C). The acid is preferably monovalent. In fact, acid HQ (see below) is generally 3
has a pka of less than 1, preferably less than 1. It has been found that particularly advantageous results are obtained from the process according to the invention when the acid chloride is a salt of an amino acid chloride. Amino acid chlorides have the formula _H2N - _R1 -COHal, where _R1 is a divalent organic group and Hal is chlorine or bromine. Such amino acid chloride salts have the formula, [H ₃ N−R ₁ −COHal] ⁺ Q ⁻ (where R ₁ and Hal are the same as above, Q ⁻ is the anion of the acid, and HQ is the above has a pka of ). The acid HQ is preferably a strong mineral acid, for example a hydrohalic acid such as hydrochloric acid or hydrobromic acid. Because of the valuable penicillin antibiotics containing the group derived therefrom, the important amino acid chloride is D-N-(α-chlorocarbonyl-α-
phenyl)-methylammonium chloride, D-
[PhCH( _NH3 )COCl]+Cl-, which is conveniently referred to herein as D-α-phenylglycyl chloride hydrochloride. obtained by this method, and the acylamide group R ^u CH
Penicillin with (NH ₂ )CONH- (where R ^u is the same as above) is a ketone R ² COR ³ (where R ² and R ³ are lower alkyl groups (C ₁ to C ₄ ))
can react with This results in a compound believed to contain . Compounds of this type include hetacillin, salpicillin, p-hydroxyhetacillin and salmoxylin. The acyl groups described in US Pat. No. 4,013,648, including columns 7-20, are also included herein and fully incorporated by reference. When the acylation process of the present invention is used to produce penicillin, the final product can be prepared by conventional methods known in the art.
Therefore, it is isolated and purified. formula (However, A is a trialkylsilyl group)
Preferred acyl chlorides used in the present method to acylate compounds having (However, A is

[expression] or

【formula】 or

[Formula], R is hydrogen, hydroxy or methoxy, R' is hydrogen or methyl, and the amino group is protected if necessary by a conventional blocking group, including in particular protonation): (However, B is

[expression] or

[expression] or

[Formula], R ¹ is hydrogen, hydroxy or acetoxy, R ² is hydrogen when R ¹ is hydroxy,
chloro or hydroxy and R ² is hydrogen if R ¹ is hydrogen or acetoxy): (However, R is phenyl, 4-hydroxyphenyl, 3,4-dihydroxyphenyl or cyclohex-1,4-dien-1-yl) (wherein R is phenyl, 4-hydroxyphenyl, 3,4-dihydroxyphenyl or cyclohex-1,4-dien-1-yl); (wherein R is phenyl, 4-hydroxyphenyl, 3,4-dihydroxyphenyl or cyclohexadien-1-yl); 〓〓〓〓〓
(However, R ¹ is phenyl, 4-hydroxyphenyl, 3,4-dihydroxyphenyl or cyclohexadien-1-yl, and R ² is hydrogen or hydroxy); (wherein R is phenyl, 4-hydroxyphenyl, 3,4-dihydroxyphenyl or cyclohexadien-1-yl); (However, A is hydrogen or alkyl of 1 to 4 carbon atoms or CH ₃ SO ₂ -, and X is oxygen or
or sulfur, and R is phenyl, 4-hydroxyphenyl, 3,4-dihydroxyphenyl or cyclohex-1,4-dien-1-yl); (However, R is hydrogen or methyl); (provided that each of R ¹ and R ² is hydrogen, chloro or fluoro); (However, B is

[Formula] or

[Formula] or

[Formula], R ¹ is hydrogen, hydroxy or acetoxy, R ² is hydrogen, chloro or hydroxy when R ¹ is hydroxy and R ² is hydrogen when R ¹ is hydrogen or acetoxy); (However, B is 〓〓〓〓〓

[expression] or

[expression] or

[Formula], R ¹ is hydrogen, hydroxy or acetoxy, R ² is hydrogen when R ¹ is hydroxy,
chloro or hydroxy, R ² is hydrogen when R ¹ is hydrogen or acetoxy, R is hydrogen or cyanomethyl); (However, B is

[expression] or

[expression] or

[Formula], R ¹ is hydrogen, hydroxy or acetoxy, R ² is hydrogen, chloro or hydroxy when R ¹ is hydroxy, R ² is hydrogen when R ¹ is hydrogen or acetoxy); (However, R is hydrogen or methyl) and the amino groups are protected, if desired, with conventional blocking groups, including inter alia protonation; 〓〓〓〓〓
(as salt if desired) (However, B is

[expression] or

[expression] or

[Formula], R ¹ is hydrogen, hydroxy or acetoxy, and R ² is hydrogen when R ¹ is hydroxy, chloro
or hydroxy and R ² is hydrogen when R ¹ is hydrogen or acetoxy); (However, B is

[expression] or

[expression] or

[Formula], R ¹ is hydrogen, hydroxy or acetoxy, R ² is hydrogen, chloro or hydroxy when R ¹ is hydroxy, R ² is hydrogen when R ¹ is hydrogen or acetoxy); (However, B is

[expression] or

[expression] or

[Formula], R ¹ is hydrogen, hydroxy or acetoxy, R ² is hydrogen, chloro or hydroxy when R ¹ is hydroxy, R ² is hydrogen when R ¹ is hydrogen or acetoxy); (However, R is hydrogen or methyl) (However, B is

[expression] or

[expression] or

[Formula], R ¹ is hydrogen, hydroxy or acetoxy, R ² is hydrogen, chloro or hydroxy when R ¹ is hydroxy, R ² is hydrogen when R ¹ is hydrogen or acetoxy); 〓〓〓
Acid chlorides are usually prepared under harsh conditions, such as by treatment of thionyl chloride with acid under reflux, but when sensitive groups are present, including seneitive protecting groups, the combination of oxalyl chloride with the acid salt Acid chlorides can be produced by reaction under practically neutral conditions. Example 1 6-aminopenicillanic acid (6-APA) and
_{CD2Cl2 10ml} and trimethylchlorosilane 1.13
1.23 ml of triethylamine was added dropwise to the 1.23 ml mixture at 25-27° C. over 30 minutes. Stirring was continued for another 2 hours. Dry carbon dioxide gas was then bubbled through the mixture for about 3 hours. At the end of this time,
The following structure in NMR (nuclear magnetic resonance) Silylated carboxy 6-APA (SCA) with
The existence of 60% was found out. This mixture was kept in the refrigerator overnight. The next day N,N
- Add 0.77 ml of dimethylaniline and mix the mixture with -8
Cooled to ℃. Then, 1.2 g of D-(-)-p-hydroxy-2-phenylglycyl chloride hydrochloride (79% purity) was added in the following proportions. Time (min) Temperature (℃) Addition (g) 0 -8 0.30 20 -4 0.30 40 -4 0.30 60 -4 0.30 120 +8 220 +5 310 +20 At the end of the 310 minute reaction, ethyl acetate 60%, acetic acid
Thin layer chromatography (TLC) performed on a sample of the reaction mixture using a solvent system of 20% water and 20% water showed the presence of amoxicillin. 1.0 ml of D ₂ O was added to a 2 ml cold sample of the final reaction mixture. After separation by centrifugation, the aqueous phase was found by NMR to contain 78% amoxicillin and approximately 20% 6-APA. TLC for the presence of amoxicillin
It was also confirmed by. Example 2 5.4 g of 6-aminopenicillanic acid in 40 ml of CH ₂ Cl ₂
(0.025 mol) and 93% hexamethyldisilazane
A mixture of 6.2 ml (HMDS, 0.0275 mol) and 0.07 g (approximately 0.001 mol) of imidazole was refluxed under nitrogen purge for approximately 17.5 hours. At the end of this time, 0.13 ml (approximately 0.001 mol) of trimethylchlorosilane (TMCS) was added. The solution became cloudy. Refluxing was continued for an additional 7 hours, and NH ₄ Cl was observed to be deposited in the condenser. At this point, NMR showed approximately 100% silylation of both the amino and carboxyl groups of 6-APA. Then
HMDS0.2ml (0.00125mol, about 5mol%) and
0.06 ml (approximately 0.0005 mol) of TMCS was added and reflux was continued for an additional 17 hours with a nitrogen purge. At this time,
The NMR spectrum was the same before addition of small amounts of HMDS and TMCS. Dry carbon dioxide was then bubbled into the reaction mixture for 75 min at room temperature, followed by NMR analysis.
No HMDS was present, showing >92% silylated carboxy 6-APA (SCA). Then N, N-
Dimethylaniline (DMA) 4.45ml (0.035mol)
was added and the mixture was cooled to -3°C. Then D-(-)-2-phenylglycyl chloride in the following proportions
5.65g (95% purity, 0.026 mole) was added. Time (minutes) Temperature (°C) Addition (g) 0 -3 1.05 20 0 1.30 40 0 1.30 50 0 1.00 60 0 1.00 The reaction was followed by NMR and showed almost no change about 5 hours after the start of the reaction. The temperature was 3°C. The reaction mixture was then kept on ice for the next 16 hours. It is then removed from refrigeration and brought to room temperature (approx.
℃) for 3.5 hours. A large amount of solid material was still present. The reaction mixture was then brought to room temperature (22-24
℃) for approximately 63 hours. At the end of this time,
〓〓〓〓〓
It was slightly cloudy. Extract the sample with _D2O ,
NMR showed ampicillin and 6-APA. The reaction mixture was cooled to about 0° C. and stirred for 5 minutes while cold after addition of 35 ml of ice water. After polishing, the mixture was washed with cold water and CH ₂ Cl ₂ . After separation, the aqueous phase is
TLC showed a large band slower than ampicillin and 6-APA, indicating that the new intermediate X
It represents. The aqueous phase was adjusted to PH 3.0 with NH ₄ OH and seeded with ampicillin. Methyl isobutyl ketone (MIBK, 35 ml) was added, the mixture was stirred, the pH was further adjusted to 5.2 with NH ₄ OH, and the mixture was incubated at 20°C for 1 hour.
Stir for an hour, stir in an ice bath for another hour,
Refrigerated overnight. Collect the ampicillin precipitate by filtration, first with 25 ml of cold water, then with 40 ml of MIBK, and finally with a mixture of 85 parts of isopropyl alcohol and 15 parts of water.
It was found to yield 4.5 g of ampicillin, which was washed with 40 ml and dried at 50° C., identified by TLC as ampicillin. Example 3 5.4 g of 6-APA in 50 ml of CH ₂ Cl ₂ , HMDS (93
%) and 0.06 g of imidazole was refluxed for 18 hours under nitrogen purge. Then, when 0.1 ml of TMCS was added, turbidity occurred. The mixture was refluxed for an additional 2 hours to obtain a clear solution, and NH ₄ Cl was deposited on the condenser. Then, 0.1 ml of TMCS was added, and a very slight turbidity remained. Reflux was continued for the next 65 hours without nitrogen purge. The mixture was then cooled to about 22°C and the addition of dry carbon dioxide was begun. After 75 minutes, NMR showed >90% bis-silylated carbamate (SCA) formation. Then, 4.45 ml of DMA was added, and 5.6 g of D-(-)-2-phenylglycyl chloride hydrochloride (97% purity) was added in the following proportions. Time (min) Temperature (°C) Addition (g) 0 20 1.35 20 20 1.30 32 20 1.00 48 20 1.00 75 20 1.00 After stirring this mixture for a further 17 hours, a reaction mixture sample and a diluted reaction mixture (2 ml of CH ₂ Cl ₂
TLC was performed on 1 ml of the diluted reaction mixture and each showed a small band of ampicillin and a large band of new intermediate X. The reaction mixture was then cooled to 0°C, 40 ml of ice water was added, the mixture was stirred for 5 minutes, and filtered through polishing.
Washed _with water and _CH2Cl2 . Separate the aqueous phase and 10%
was removed as a sample, and the remainder was adjusted to pH 3.0 with NH ₄ OH, and ampicillin seeds were added and stirred. After adding another 40ml of MIBK, stir the mixture.
The pH was adjusted to 5.2 with NH ₄ OH and stirred at room temperature for 1 hour and in an ice bath for an additional hour. Crystals precipitated. After overnight refrigeration, the crystalline product was collected by filtration.
MIBK, water, MIBK, isopropanol-water (85
Pair 15) was washed with 40 ml of water and dried at 45°C to obtain 6.25 g of ampicillin. (6.8g, 68% corrected for sample use)
yield). Example 4 1.0 g of 6-APA in 10 ml of CD ₂ Cl ₂ and
1.23 ml of TEA was added dropwise to the 1.13 ml TMCS mixture over 30 minutes and the mixture was stirred for an additional 2 hours. Dry carbon dioxide was then bubbled in for 4 hours. At this time NMR showed about 55-60% carboxysilylation. The mixture was then refrigerated overnight. morning
Add 0.77 ml of DMA, stir the mixture, cool to -8°C and add D-(-)-p-hydroxy-2 in the following proportions.
- 1.2 g of phenylglycyl chloride hydrochloride was added. Time (min) Temperature (°C) Addition (g) 0 -8 0.30 20 -4 0.30 40 -4 0.30 60 -4 0.30 120 8 220 15 310 20 3 At the end of 10 minutes, NMR is about 78% of amoxicillin
and 6-APA about 20%. Example 5 Dry 6-aminopenicillanic acid (10.0 g, 46.24 mmol, 1.0 eq.) was dissolved in anhydrous methylene chloride (175 ml).
The mixture was stirred and suspended at 25°C. Triethylamine (10.76 g, 106.36 mmol, 2.30 eq.) was added at 25°C, followed by trimethylchlorosilane (11.70 g, 107.75 mmol, 2.33
equivalent amount) was added over 10-15 minutes. After stirring for 20-30 minutes, the mixture containing precipitated triethyl hydrochloride is
Completely silylated by 80MHz NMR〓〓〓〓〓
analyzed. Carbon dioxide gas was then passed through the mixture at 20° C. for about 2 hours, and the mixture was analyzed for complete carboxylation by 80 MHz NMR. Sometimes it was necessary to introduce additional carbon dioxide gas. If necessary, the volume of the carboxylation mixture was readjusted to approximately 175 ml with dry methylene chloride. After the carboxylation is complete, the slurry is treated with propylene oxide (2.95 g, 3.56
ml, 50.87 mmol, 1.1 eq.), 0-5
Cooled to ℃. D-(-)-2-(p-hydroxyphenyl)glycyl chloride hydrochloride hemidioxane solvate was added in 5 x 2.71 g portions at about 2°C [total 13.54 g (50.87 mmol, 1.1 eq.) ]. Each portion of the acid chloride was allowed to dissolve ^* before adding the next portion. This took approximately 20 minutes per portion. This stepwise addition was of significant importance. The final acylation mixture was checked for undissolved acid chloride hydrochloride. The mixture was kept at 0-5 °C for 30 min and diluted with cold (0-5 °C) deionized (DI) water (100 ml) for 10 min.
Processed by stirring at high speed for 1 minute. allowing the mixture to separate;
The lower layer of methylene chloride was removed. Polish the aqueous mixture (almost no solids) through a thin (guicalite) precoat of diatomaceous earth;
The cake was washed with cold (0-5°C) DI water (15ml). The underlying organic layer was removed before crystallization. A clear pale yellow aqueous solution (PH 2-2.5) was adjusted to PH 3.5 at 0-5°C, and seeds were added if necessary. This slurry is 0~
Keep at 5℃ for 40 minutes and adjust pH with 6N ammonium hydroxide.
It was adjusted to 4.8-5.0 and crystallized for 2 hours. Filter the slurry and wash the solid amoxicillin thus collected with a cold (0-5°C) 1:1 isopropanol/water mixture and wash the cake with methylene chloride (30 ml) to give approximately 13.5 g of snow-white amoxicillin trihydrate.
(approximately 70%). * Stop stirring and examine the mixture for solids at the bottom of the flask. In this test, the slurry
Do not heat above °C or the results will be erroneous. Example 6 108 g (0.5 mol) of 6-aminopenicillanic acid, 1.0 g (0.017 mol) of imidazole, dry methylene chloride
800ml, HMDS (approximately 98% purity) 120ml (0.56 mol)
The mixture was stirred and heated under reflux for 3.3 hours. The reaction was purged with dry nitrogen gas at reflux to sweep away the NH ₃ produced in the reaction. Then 2.0 ml (0.016 mol) of trimethylchlorosilane (TMCS) was added.
Continue refluxing for another 19 h while purging with _N2 .
Next, cleanly remove the sublimed NH ₄ Cl in a cooler,
2.6 ml (0.0206 mol) of TMCS was added to the reaction. _N2
Refluxing was continued for an additional 34 hours while purging with water. The reaction mixture volume was made up to 1000 ml with dry methylene chloride. NMR then showed 100% silylation of the amino and carboxyl groups of 6-aminopenicillanic acid. The solution was blanketed with _N2 gas and kept for 9 days. The above stability was confirmed by NMR. The solution was stirred and _CO2 was bubbled through for approximately 90 minutes. temperature is 20
It was ~22℃. Bistrimethylsilyl 6-aminopenicillanic acid is converted to bistrimethylsilylcarboxy 6-aminopenicillanic acid (SCA) by NMR.
It turned out that the conversion was 100%. This master mix was used in the acylation experiments described below. The chemical in this solution had the following structural formula: NMR is bistrimethylsilylcarboxy 6-
Aminopenicillanic acid was shown to be stable after 9 days. 100 ml of this master mixture (SCA equivalent to 10.8 g of 6-aminopenicillanic acid, 0.05 mol) was stirred at 22°C, mixed with 8.0 g (0.058 mol) of TEA.HCl and 4.2 ml (0.06 mol) of propylene oxide (U.S. Pat.
3741959) was added. Some TEA/HCl
was precipitated. The mixture was stirred and cooled to +3°C. Add 15.5 g of D-(-)-p-hydroxyphenylglycyl chloride hydrochloride hemidioxane solvate (purity 79%, 0.055 mol) to the reaction in the following proportions.
Ta. Addition (g) Time (min) Temperature (°C) 3.0 0 +3 3.0 7 +2 3.0 20 +2 6.5 33 +2 15.5 After a further 70 minutes approximately 50 ml of dry methylene chloride was added to the reaction mixture to reduce the viscosity. After another 160 minutes, 2 ml of sample was taken out and D ₂ O1.0
Added to ml. After centrifugation, NMR analysis of the aqueous phase showed approximately 6% unacylated 6-aminopenicillanic acid. After 10 minutes, the reaction mixture was transferred to a 600 ml beaker and washed with 50 ml of methylene chloride to complete the transfer. Cool deionized ice water with stirring in an ice bath for 60 min.
ml was added to obtain a two-phase solution free of solids and having a pH of 1.0. 15.0 ml of liquid anion exchange resin (LA-1) was stirred and added to this two-phase system, and the seeds were added at pH 2.0. Crystallization has begun. Furthermore, 10.0 ml of LA-1 was gradually added over about 5 minutes. The pH was 3.0. Then 0.15 g of NaBH ₄ was added. Then LA-
Added 15.0ml. The pH was 4.5. Stirring was continued and 1.0 g of NaHSO ₃ (sodium bisulfite) in 4.0 ml of water was added dropwise. Then, 10.0 ml of LA-1 was added. PH continued to rise. Total LA-1 40ml
The final pH was 5.6. Then 5ml of acetone
added. At this point dissolved in 6.0ml of water
1.5g of _NaHSO3 was added over 30 minutes. Stirring was continued in the ice bath. Collect the precipitated product by filtration,
The cake was washed sequentially with 50 ml methylene chloride, 40 ml water, 100 ml isopropyl alcohol-water (80:20), and 100 ml methylene chloride. Add the cake and cook at normal pressure for 45 minutes.
Dry at ℃ to obtain 18.2 g of amoxicillin trihydrate;
This was an 87% yield for 6-aminopenicillanic acid, and when corrected for 1% sampling the overall yield was approximately 88%. In LA-1 liquid anion exchange resin, each secondary amine has the following structural formula: (However, each of R ¹ , R ² .R ³ is an aliphatic hydrocarbon group, and R ¹ , R ² , R ³ as a whole contains 11 to 14 carbon atoms) It is a mixture of amines. Sometimes “Liquid Amine Mixture No. 1”
This particular mixture of secondary amines, called , is a clear amber liquid with the following physical properties:
Viscosity at 25℃ 70cps, specific gravity at 20℃ 0.845, refractive index at 25℃ 1.467, distillation range at 10mm, 4% up to 160℃,
160-210℃ 5%, 210-220℃ 74%, 220℃ or above 17
%. Example 7 Trimethylsilyl 6-trimethylsilyloxycarbonylaminopenicillinate (0.54 g, 2.497
A methylene chloride solution (5.0 ml) of 0.2 mmol) was treated with triethylamine hydrochloride (0.20 g, 1.45 mmol) followed by propylene oxide (0.162 g,
2.75 mmol) at 25°C. The mixture was stirred at 25° C. for 20 minutes to facilitate dissolution of most of the triethylamine hydrochloride. Phenoxyacetyl chloride (0.43 g, 2.75 mmol) was added dropwise at 25°C and the mixture was stirred at 25°C for 30 minutes. A sample was taken and analyzed by CMR at 20.0MHz. CMR ( ^C13 Nuclear Magnetic Resonance Spectrum) data showed complete disappearance of phenoxyacetyl chloride and APA carbamate and appearance of penicillin V trimethylsilyl ester. The presence of penicillin V trimethylsilyl ester was demonstrated by spectral comparison with the same sample prepared by silylation of penicillin V free acid with triethylamine and trimethylchlorosilane. The yield estimated from the CMR spectrum was 85-90%. Cloxacillin, dicloxacillin, stafcillin, and nafcillin were prepared similarly using the same molar amounts of reagents and the appropriate acid chloride. CMR data for these acylation mixtures are at least 85
It showed a very clean acylation mixture with a yield estimated at %. Example 8 Formula〓〓〓〓〓
(However, B is a trialkylsilyl group)
reaction with a suitable acid chloride or acid chloride hydrochloride reagent (containing a blocking group if necessary) according to the procedure described above, followed by removal of the blocking group from which removal is desired. The following compounds were produced by: almecillin, armecillin, azidocillin, azlocillin, bacampicillin, formula Bay K4999 with the formula BL−P1654 with formula BL-P1908, carfecillin, carindacillin,
cyclacillin, clomethocillin, cloxacillin,
Dicloxacillin, formula〓〓〓〓〓
EMD-32412, epicillin, with
floxacillin, (flucloxacillin), flubucillin, hetacillin, formula ISF-2664, isopropicillin, methicillin, mezlocillin, nafcillin, oxacillin, phenbenicillin, with the formula PC−455 with the formula aparcillin (PC-
904), piperacillin, 3,4-dihydroxypiperacillin (3,4-
dihydroxypiperacillin), pirbenicillin, pivampicillin, formula〓〓〓〓〓
PL-385, prazocillin, sarmoxicillin, sarpicillin,
Ticarcillin resin sodium (ticarcillin)
cresyl sodium), ticarcillin, carbenicillin, carfecillin, fibracillin and formula Bay-e-6905 with The present invention can be applied industrially. 〓〓〓〓〓

Claims (1)

[Claims] 1 formula (However, B is a trialkylsilyl group)
The compound shown in 2 formulas The compound according to claim 1, which is represented by: 3 formula〓〓〓〓〓
(However, B is a trialkylsilyl group)
consisting of adding dry carbon dioxide in an anhydrous inert organic solvent at a temperature ranging from 0 °C to 100 °C until reaction completion to a solution of a compound having the formula (However, B is the same as above.) A method for producing a compound. 4. The manufacturing method according to claim 3, wherein B is a trimethylsilyl group.