WO2015070394A1

WO2015070394A1 - Method for preparing penem antibiotic intermediate

Info

Publication number: WO2015070394A1
Application number: PCT/CN2013/087038
Authority: WO
Inventors: 洪浩; 马建国; 李九远; 董长明; 张磊
Original assignee: 凯莱英医药集团（天津）股份有限公司; 凯莱英生命科学技术(天津)有限公司; 天津凯莱英制药有限公司; 凯莱英医药化学（阜新）技术有限公司; 吉林凯莱英医药化学有限公司
Priority date: 2013-11-13
Filing date: 2013-11-13
Publication date: 2015-05-21

Abstract

The present invention relates to a method for preparing a penem antibiotic intermediate. The method comprises the following steps: step 1: preparing an intermediate compound by means of a Mannich reaction; and step 2: converting the intermediate compound into a penem antibiotic intermediate. The method shortens the reaction period, reduces the cost, and reduces environmental pollution, and reaction materials are easily obtained; and the selectivity and the yield of the method are remarkably improved in comparison with the prior art.

Description

Method for preparing perennial antibiotic intermediates

The invention relates to the field of synthesis of pharmaceutical intermediates, in particular to a preparation method of a Pein-like antibiotic intermediate. Background technique

Pein-type drugs such as meropenem, doripenem and ertapenem are a class of broad-spectrum antibiotics for β-lactam injection. It is well known that the compound represented by the formula (la) is a card catalyzed by ruthenium.

The synthetic route shown in Reaction Scheme 2 is currently widely used. The compound of the formula (la) can be subjected to CDI activation, nucleophilic addition reaction and decarboxylation reaction, and removal of TBS (t-butyl group) by β-methyl-ADC-8 (4-oxime, compound of formula (V)). Dimethylsilyl hydrazine and the diazotization reaction involving t-decylbenzenesulfonyl azide are conveniently prepared. 0. Am. Chem. Soc, 1980, 102 6161-6163). A difficulty with this route is the preparation of a compound represented by the chiral β-methyl formula (V).

4-Acetylazetidinone (4AA, a compound of formula (VIII)) is generally used to prepare 4-BMA (reviewed in detail: Tetrahedron, 1996, 52, 33 1 -375). For example, a compound of the formula (IX) having a terminal double bond is prepared from 4AA, and then 4-BMA (US53 10897, US4873324, EP230792, reaction formula 3) can be produced in a high yield and high selectivity by an asymmetric hydrogenation reaction. However, the preparation of the compound of the formula (IX) is difficult.

Reaction Scheme 3 Another route for the preparation of 4-BMA by 4AA is the use of a pro-radical-induced asymmetric Reformatsky reaction. A variety of prosthetic groups have been reported to have good β-selectivity (US4791207, US5104984, EP197432, JP06065195). However, the synthesis and removal of the prosthetic group requires additional steps, resulting in increased costs.

XI XII XIII

Another method is developed by Merck.

Lett. 1994, 35, 2275-2278). The compound of the formula (XIV) can be obtained by a series of reactions of 4AA by a coupling reaction of isopropylidene methylmalonate, N-silylation and solvolysis of methyl isopropylidene malonate. The acid-catalyzed asymmetric hydrolysis and removal of the protecting group can then give 4-indole at a β-selectivity of >10:1.

Reaction Formula 5 Bristol-Myers Squibb reported a series of preparations prepared by direct Mannich reaction from 4AA. Route of a compound of formula (I) or an analogue thereof

Letters, 1987, 28, 507-510; Tetrahedron Letters, 1988, 29, 61-64; Can. J. Chem. 1988, 6, 1400-1404). However, these reactions all result in very low β-selectivity or very low yield.

ZnCI ₂ : 78:22 β selectivity, 75% yield

MgCI ₂ : 60:40 β selectivity, 26% yield

4ΑΑ 4 5

SnCI ₂ : 69:31 β selectivity, 70% yield

TMSOTf: 57:43 β selectivity, 75% yield

MgBr ₂ : 83:17 β selectivity, 8% yield reaction formula 6 In the course of continuous development of a new route for the preparation of the compound of the formula (IVa) and its analogous compounds, the inventors of the present invention found a commercial value. And a synthetic route with shorter synthesis steps and simple chemistry. The technical content of the present invention is not found in previous reports and work. Summary of the invention

SUMMARY OF THE INVENTION A primary object of the present invention is to provide a simple and commercially valuable synthetic route for the preparation of a compound of the formula by a two-step reaction of a compound of formula (II).

Another object of the present invention is to provide a high β-selective method for direct Mannich addition of a compound of the formula (II) using a compound of the formula σιι).

In addition, the present invention also provides optimum reaction conditions for the Mannich reaction. The present invention provides a process for preparing a penicillin antibiotic intermediate represented by the chemical formula σ), which comprises the steps shown in Reaction Scheme 7.

In the present invention, the compound represented by the chemical formula σ) is abbreviated as the compound σ), and the other compounds are also referred to as corresponding abbreviations.

In the present invention, the following substances are replaced by their corresponding abbreviations:

TMS: trimethylsilyl;

TBS: tert-butyldimethylsilyl;

ΡΝΒ : p-nitrobenzyl;

Me: methyl;

Et: ethyl;

Bz: benzoyl;

Ac: acetyl group;

Bn: benzyl;

Allyl: allyl.

In Reaction Scheme 7, the functional group represented by R ¹ includes, but is not limited to, methyl (Me), ethyl (Et), p-nitrobenzyl (PNB), benzyl (Bn), allyl (Allyl), 4-chlorobenzyl, 2-nitrobenzyl, 3-nitrobenzyl, 4-methoxybenzyl;

The functional group represented by R ² includes, but is not limited to, acetyl (Ac), benzoyl (Bz);

The functional groups represented by R ² include, but are not limited to, trimethylsilyl (TMS), tert-butyldimethylsilyl (TBS).

The compound of the formula (III) can be easily synthesized by a conventional method.

The content in Equation 7 consists essentially of two steps:

Step h The compound of the formula (Π) is reacted with a compound of the formula σιι) to obtain a compound of the formula (XVI);

Step 2: The compound represented by the chemical formula (XVI) is prepared, that is, β- Methylpenic antibiotic intermediate.

Steps 1 and 2 are carried out according to the following reaction conditions:

For step 1, the reaction can be carried out under a variety of known Lewis acid catalyzed direct Mannich reactions. After the reaction is completed, various methods can be used for post treatment.

The Lewis acid used in the Mannich reaction may be any of the existing acids used in the Mannich reaction, including but not limited to titanium tetrachloride (TiCl ₄ ), titanium tetrabromide (TiBr ₄ ), silicon tetrachloride (SiCl _{4 ).} ), lanthanum trichloride (LaCl ₃ ), zinc chloride (ZnCl ₂ ), zinc bromide (ZnBr ₂ ), magnesium chloride (MgCl ₂ ), boron tribromide (BBr ₃ ), copper chloride (CuCl ₂ ), Copper triflate (Cu(OTf) ₂ ), cuprous triflate (CuOTf), cuprous iodide (Cul), boron trichloride (BC1 ₃ ), etc., preferably using relatively inexpensive four Titanium chloride (TiCl ₄ ).

The molar ratio of the Lewis acid to the compound of the formula (II) is 0.8 to 3.0:1, preferably 1.0 to 1.5: l o If less Lewis acid is used, the reaction cannot be completed.

A Lewis base is also present in the reaction of step 1. The Lewis base may be any of the bases currently used in the Mannich reaction, including but not limited to triethylamine, diisopropylethylamine, tri-n-butylamine, tetramethylethylenediamine, 4-methylmorpholine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane, 4-dimethylaminopyridine, N-methyl Pyrrolizine, N-methylpiperidine, diethylamine, diisopropylamine, pyrrole, piperidine, hexamethylphosphoric triamide, pyridine, 3-methylpyridine, and combinations thereof. It is preferred to use a tertiary amine therein.

The molar ratio of the Lewis base to the compound of the formula (II) is from 1.2 to 4.0:1, preferably

1.8-2.5: 1.

As a preferred technical solution, the reaction of the step 1 is usually carried out by dissolving the compound of the formula in an organic solvent, cooling, then adding a Lewis acid and a Lewis base, stirring, adding a compound of the formula (Π), and then reacting until the end.

The solvent includes methylene chloride, 1,2-dichloroacetonitrile, toluene, acetonitrile, tetrahydrofuran, methyl t-butyl ether, 2-methyltetrahydrofuran or a combination thereof. Preferably, methylene chloride, 1,2-dichloroethane or a combination thereof is used.

The solvent is used in an amount of 8 to 30 mL/g based on the compound of the formula (Π) (i.e., 8 to 30 mL of the solvent per gram of the compound represented by the formula (Π), preferably 12 to 20 mL/g.

The molar ratio of the compound of the formula (III) to the compound of the formula (Π) is 1.0 to 2.0: 1, preferably 1.2 to 1.5: 1.

The reaction temperature in the step 1 is -60 to 10 ° C, preferably -30 to 0 ° C.

Specifically, a suitable temperature for the addition of the Lewis acid and the Lewis base is -60 to 0 ° C, preferably -50 to 30 ° C. The appropriate stirring time before the addition of the compound of the formula (II) should be 10 to 60 minutes, preferably 20 to 30 minutes. A suitable temperature for the addition of the compound of the formula (II) is -60 to 0 ° C, preferably -40 to 20 ° C. A suitable temperature for the reaction is -40 to 10 ° C, preferably -20 to 0 ° C. The reaction will proceed very slowly at lower temperatures. The appropriate reaction time should be within 4 hours and, if possible, the reaction should be completed within 2.5 hours. Longer reaction times result in more impurities and lower yields.

After completion of the reaction, the reaction is quenched with an aqueous solution such as aqueous sodium chloride solution, aqueous sodium hydrogencarbonate solution, aqueous sodium dihydrogen phosphate solution, aqueous potassium dihydrogen phosphate solution, aqueous magnesium chloride solution, aqueous calcium chloride solution or purified water, preferably using pure water. Wherein, the concentration of the aqueous solution is a concentration of a common quenching solution, and preferably the mass percentage of the solute may be 5% to 25%.

The amount of the quenching solution is 3 to 30 mL/g, preferably 5 to 10 mL/g, based on the compound of the formula (Π).

The compound of the formula (XVI) obtained in the step 1 can be directly used for the next reaction, or can be further purified, preferably using methanol, methanol-water, ethanol, ethanol-water, acetone, acetone-water, acetonitrile. Solvents such as isopropanol, n-hexanol, n-glycol, toluene, petroleum ether, etc. are purified by recrystallization, more preferably by recrystallization from methanol-water. The amount of the recrystallization solvent is from 3 to 20 mL/g, preferably from 4 to 8 mL/g, based on the compound of the formula (II). Using more solvent will reduce the yield.

For the step 2, the reaction can be carried out under various reaction conditions in which the acid is removed by the removal of the t-butyldimethylsilyl group or the trimethylsilyl group. After the completion of the reaction, various methods can be used for the post treatment.

The acid used for removing tert-butyldimethylsilyl or trimethylsilyl protection includes hydrochloric acid (HC1), sulfuric acid (H ₂ S0 ₄ ), methanesulfonic acid (MeS0 ₃ H), benzenesulfonate. Acid (PhS0 ₃ H) and trifluoroacetic acid, preferably hydrochloric acid.

The concentration of the hydrochloric acid for protecting the tert-butyldimethylsilyl or trimethylsilyl group is 0.5-4 mol/L, preferably 1.0 to 2.0 mol/L.

The reaction of the step 2 is carried out in a solvent selected from the group consisting of a mixed solvent of acetonitrile-water, methanol-water, acetone-water, tetrahydrofuran-water, etc., wherein the volume concentration of the organic solvent ranges from 40% to ~ 80%, preferably an acetonitrile-water solution having a volume concentration of 40% to 80% acetonitrile is used as a reaction solvent. The amount of the solvent used is 4 to 15 mL/g, preferably 6 to 10 mL/g, based on the compound of the formula (XVI).

The suitable temperature for the step 2 reaction is 0 to 30 ° C, preferably 15 to 20 ° C.

Compared with the prior route, the preparation method provided by the present invention has obvious advantages. The reaction step is greatly shortened, and it is required to prepare a compound represented by the chemical formula σ) from the compound represented by the chemical formula σι)

Compared with the 5~7 steps, the preparation method used in the present invention requires only 2 steps, so the reaction cycle is greatly shortened, labor costs are saved, equipment investment for commercial production is reduced, and the types and amounts of solvents used are reduced. The pollution is also relatively reduced, while saving the production costs of the factory. The preparation method of the present invention is easily obtained as a raw material, and the selectivity and yield of the obtained product are remarkably improved as compared with the prior art. detailed description

The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention. Unless otherwise specified, the reagents used in the examples are conventional commercially available reagents, and the technical means used in the examples are conventional means well known to those skilled in the art.

Example 1

(1) Preparation of a compound of the formula (XVIa)

Compound (Ilia) is synthesized by reference to US 4644061 A1 (1987).

The compound of formula (Ilia) (188 g) was dissolved in dichloromethane (1500 mL), cooled to -40 ° C, and titanium tetrachloride (104 g) in dichloromethane (300 mL) was slowly added. The resulting yellow slurry was stirred for a further 30 minutes. Triethylamine (105 g) was slowly added, then the reaction mixture was warmed to -20 ° C and stirring was continued for 1 hour, then a solution of 4AA (150 g) in dichloromethane (300 mL) was slowly added. After stirring at -20 °C for 3 hours, the reaction was warmed to 5 ° C then quenched with water (750 mL). The layers were allowed to stand, the methylene chloride phase was separated, and a layer of silica gel (75 g) was filtered and concentrated. HPLC showed the product in the reaction system to have a β/α ratio of 8.8:1. The residue was washed with methanol (300 mL), filtered The compound of the formula (XVIa) has a liquid phase purity of 80% and a β/α ratio of 30:1, which is directly used in the next reaction.

NMR NMR (400 MHz, CDC1 ₃ ): δ 8.22 (d, J = 8.7 Hz, 2H), 7.51 (d, J = 8.6 Hz, 2H), 6.10 (s, IH), 5.33 (s, 2H), 4.18 -4.12 (m, IH), 3.92-3.86 (m, 2H), 2.94 (d, J=4.3 Hz, IH), 1.17-1.15 (m, 6H), 0.83 (s, 9H), 0.04 (d, J = 5.2 Hz, 6H).

(2) Preparation of a compound of the formula (la)

The compound of formula (XVIa) (51 g) is suspended in acetonitrile with 40% by volume of acetonitrile.

In an aqueous solution (300 mL), 1NHC1 (100 mL) was added at 15 to 20 °C. The reaction was stirred at 15 to 20 ° C until the reaction was complete. Add 300 mL of ethyl acetate and adjust the pH of the aqueous phase to 6-7 with saturated sodium bicarbonate. The organic phase was separated, washed with 150 mL of brine, concentrated, 150 mL of toluene, and filtered to give the compound of formula (la) (36 g, yield 92.3%), liquid phase purity >97% .

lR NMR (400 MHz, CDC1 ₃ ): δ 8.25 (d, J = 8.7 Hz, 2H), 7.53 (d, J = 8.7

Hz, 2H), 6.25 (br, IH), 5.35 (s, 2H), 4.13-4.17 (m, IH), 3.88 (dd, J= 8.5, 2.0

Hz, IH), 3.62 (dd, J= 8.3, 7.2 Hz, IH), 2.96 (d, J= 4.5 Hz, IH), 2.89 (dd, J

= 6.0, 2.0 Hz, IH), 1.30 (d, J = 8.4 Hz, 3H), 1.20 (d, J = 8.4 Hz, 3H).

Example 2

(1) Preparation of a compound of the formula (nib)

Add p-chlorobenzyl alcohol (100 g), methyl 3-oxopentanoate (100 g) and toluene at about 20 °C

(300 mL), heated to reflux, and the solvent was distilled off using an atmospheric distillation apparatus until the temperature of the system rose to 150. ° ° CC. . Repeatingly repeating 33~~44 times, the obtained crude chemical product of the chemical compound formula ((XXVVIIIIbb)) is directly used for the next step. Step reaction should be. .

The crude crude product of the chemical compound represented by the above-mentioned chemical formula ((XXVVIIIIbb)) is added at about 2200 ° ° CC, toluene benzene ((330000 mm LL) And triethyltriethylamine ((3355..44 gg)), and then post-drip plus p-dodecyldiphenylbenzenesulfonyl-lacide azide nitrogen (227700 ..44 gg)). . After the drop is completed, 5 will return to the room temperature and the reaction should be 55 hours. . The reaction system is concentrated and concentrated to about 220000~~330000 mmLL, and then added to the positive gengbeng ((550000 mmLL)), and the ice-cold water bath is cooled by cooling and stirred. Mix about 55 hours. . After filtering through the filter, the filter cake is washed and washed with Zheng Geng Geng, dried and dried to obtain the chemical compound represented by the chemical formula ((nniibb)) ((112266) Gg,, yield yield: 6677%%)), liquid-liquid phase purity purity 9999..44%%. .

l ^l RR NNMMRR ((440000 MMHHzz,, CCDDCC11 ₃₃ )):: δδ 77..3366 ((dd,, JJ == 88..55 HHzz,, 22HH)),, 77..3300 ((dd,, JJ == 88..55 HHzz,, 22HH)),, 55..2222 ((ss,, 22HH)),, 22..8866 ((qq,, JJ == 77..33 HHzz,, 22HH) ),, 11..1144 ((tt,, JJ == 77..33 HHzz,, 33HH)). .

Chemical compound formula ((IIllllbb)) shown in the chemical compound ((2255 dissolved in dichlorochloromethylformamidine ((228800 mmLL)), cold cooling to 1155 --4400 ° ° CC,, slowly and slowly added to the titanium tetrachloride titanium chloride ((1133..22 gg)), the obtained yellow-yellow color slurry Continue to stir and stir for 3,300 minutes.

Slowly and slowly add tributyl triethylamine ((1144..11 gg)), and then the reaction should be raised to -2200 ° ° CC and continue to stir and stir. At 11 hours, then slowly and slowly add 44AAAA ((2200 gg)) of dichlorochloromethane ((4400 mmLL)) solution. . After stirring for 33 hours at -2200 ° ° CC, the reaction product will be warmed to room temperature, and then water ((115500 mm LL)) Quenching and extinction. . The layer was layered quietly, and the phase of dichlorochloromethane was separated out, and then concentrated and concentrated. . The remaining residue was purified by column chromatography using silica gel column chromatography to obtain the chemical compound represented by the chemical formula ((XXVVIIbb)) ((1177..00 2200 gg, 4499) %% yield rate)), ββ//αα ratio is 77..33::11. .

^{^!!} HH ^{NNMMRR ((ββ} isomer thereof iso isomers)) ((440000 MMHHzz ,, CCDDCC11 33)) :: δδ 77..3355 ((άά ,, JJ == 88..55 HHzz ,, 22ΗΗ)) ,, 77..3300 ((dd,, JJ == 88..44 HHzz,, 22HH)),, 55..9922 ((ss,, 11HH)),, 55..2211 ((dd,, JJ == 22..11HHzz,, 22HH)),, 44..1199--44..1144 ((mm,, 11HH)),, 33..9922--33..8877 ((mm,, 22HH) ),, 22..9955 ((dddd,, JJ == 44..00,, 11..88 HHzz,, 11HH)),, 11..1188--11..1155 ((mm,, 66HH) ),, 00..8844 ((ss,, 99HH)),, 00..0044 ((dd,, JJ == 66..00 HHzz,, 66HH)). .

2255 *

The compound of the formula (XVIb) (15 g) was suspended in an acetonitrile-water solution (100 mL) of 40% by volume of acetonitrile, and IN HCl (36 mL) was added at 15 to 20 °C. The reaction was stirred at 15 to 20 ° C until the reaction was completed. 120 mL of ethyl acetate was added and the pH of the aqueous phase was adjusted to 6-7 with saturated sodium bicarbonate. The organic phase was separated, washed with 45 mL of brine, concentrated, and purified by silica gel column chromatography to give the compound of formula (lb) (11.4 g, 100% yield) with a ratio of 7.3:1.

^! H NMR _{^(β-isomer) (400 MHz, CDC1 3)} : δ 7.37 (ά, J = 8.4 Hz, 2Η),

7.29 (d, J= 8.4 Hz, 2H), 6.74 (br, 1H), 5.28 (s, 2H), 4.04-4.09 (m, 1H), 3.80 (dd, J= 6.4, 2.1 Hz, 1H), 3.69 -3.75 (m, 1H), 2.85 (dd, J= 6.6, 1.8 Hz, 1H),

2.67 (brs, 1H), 1.22 (d, J = 6.3 Hz, 3H), 1.17 (d, J = 6.3 Hz, 3H).

Example 3

(1) Preparation of a compound of the formula (Hie)

Methyl 3-oxopentanoate (30 g), toluene (150 mL) and triethylamine (11.6 g) were added at about 15 ° C, then p-dodecylbenzenesulfonyl azide (89.1 g) was added dropwise. After the dropwise addition, the mixture was naturally returned to room temperature for 5 hours. The reaction system was concentrated to a fraction. The crude product was purified by silica gel column chromatography to give the compound of formula (IIIc) (33.8 g, yield 94%), and the liquid phase purity was 98.5%.

^{1 Ί Ά NMR (400 MHz,} CDC1 3): δ 3.83 (s, 3H), 2.86 (q, J = 7.3 Hz, 2H),

1.14 (t, J = 7.3 Hz, 3H

(2) Preparation of a compound of the formula (XVIc)

The compound of the formula (IIIc) (14.1 g) was dissolved in dichloromethane (280 mL), cooled to -40 ° C, titanium tetrachloride (13.2 g) was slowly added, and the resulting yellow slurry was stirred continuously. minute. Triethylamine (14.1 g) was slowly added, then the reaction mixture was warmed to -20 ° C and stirring was continued for 1 hour, and then a solution of 4AA (20 g) of dichloromethane (40 mL) was slowly added. After stirring at -20 °C for 3 hours, the reaction was warmed to EtOAc EtOAc. The layers were allowed to stand, the methylene chloride phase was separated, and then concentrated. The residue was purified by silica gel column chromatography toield of compound of formula (XVIc) (11.5 g, 43% yield). The ratio of β/α was 4.2:1.

^ NMR (β isomer) (400 MHz, CDC1 ₃ ): δ 5.97 (brs, 1Η), 4.17-4.19 (m, 1H), 3.85-3.94 (m, 1H), 3.84 (s, 3H), 2.92 (dd, J = 3.9, 1.8 Hz, 1H), 1.17-1.20 (m, 6H), 0.88 (s, 9H), 0.07 (d, J = 6.0 Hz, 6H).

(3) Preparation of a compound of the formula (Ic)

The compound of formula (XVIa) (10 g) was suspended in acetonitrile with 40% by volume of acetonitrile.

- In an aqueous solution (80 mL), at 15-20. Add IN HC1 (30 mL) to C. The reaction is at 15-20. Stir under C until the reaction is complete. Add 100 mL of ethyl acetate and adjust the pH of the aqueous phase to 6-7 with saturated sodium bicarbonate. The organic phase was separated, washed with 50 mL of brine, concentrated, and purified by silica gel column chromatography to give the compound of formula (lb) (7.16 g, 100% yield). The ratio of β/α was 4.2:1.

^ NMR (β isomer) (400 MHz, CDC1 ₃ ): δ 6.65 (brs, 1Η), 4.04-4.09 (m, 1H), 3.69 (s, 3H), 3.80 (dd, J= 6.4, 2.1 Hz , 1H), 3.69-3.75 (m, 1H), 2.85 (dd J = 6.6, 1.8 Hz, 1H), 2.65 (brs, 1H), 1.24 (d, J = 6.3 Hz, 3H), 1.17 (d, J = 6.3 Hz, 3H) o Example 4

(1) Preparation of a compound of the formula (Hid)

Add o-nitrobenzyl alcohol (107 g), methyl 3-oxopentanoate (100 g) and toluene at about 25 °C

(300 mL), heated to reflux, and the solvent was distilled off using an atmospheric distillation apparatus until the temperature of the system was raised to 150 °C. The crude product of the obtained compound of the formula (XVIId) was directly used in the next reaction 3 to 4 times.

The crude compound of the above formula (XVIId), toluene (300 mL) and triethylamine (35.4 g) were added at about 25 ° C, then p-dodecylbenzenesulfonyl azide (270.4 g) was added dropwise. After the completion of the dropwise addition, the reaction was naturally returned to room temperature for 5 hours. The reaction system was concentrated to about 200 to 300 mL, then n-glycol (500 mL) was added, and the mixture was cooled and cooled in an ice water bath for about 1 hour. After filtration, the filter cake was washed with n-glycol and dried to give a compound of the formula (Hd) (151 g, yield 78%), and the liquid phase purity was 99.6%.

!H NMR (400 MHz, CDC1 ₃ ): δ 8.08-8.18 (m, 1Η), 7.64-7.75 (m, 1H), 7.46-7.59 (m, 2H), 5.67 (s, 2H), 2.86 (q, J = 7.3 Hz, 2H), 1.15 (t, J = 7.3 Hz, 3H) o

(2) Preparation of a compound of formula (Id)

The compound of formula (Illd) (23.1 g) was dissolved in dichloromethane (280 mL) and cooled to

Titanium tetrachloride (13.2 g) was slowly added at -40 ° C, and the resulting yellow slurry was stirred for further 30 minutes. Triethylamine (14.1 g) was slowly added, then the reaction mixture was warmed to -20 ° C and stirring was continued for 1 hour, then a solution of 4AA (20 g) of dichloromethane (40 mL) was slowly added. After stirring at -20 ° C for 3 hours, The reaction was warmed to rt then EtOAc (EtOAc)EtOAc. The mixture was allowed to stand for separation, the methylene chloride phase was separated, and then concentrated to give a crude product of the formula (XVId).

The crude product (44.2 g) of the compound of formula (XVId) was suspended in 50% acetonitrile solution.

(120 mL), in 15~20. Add 3N HC1 (40 mL) to C. The reaction is at 15-20. Stir under C until the reaction is complete. 120 mL of ethyl acetate was added and the pH of the aqueous phase was adjusted to 6-7 with saturated sodium bicarbonate. The organic phase was separated, washed with 45 mL of brine, concentrated, and purified by silica gel column chromatography to give the compound of formula (Id) (12.2 g, two-step 45% yield) with a ratio of 8.5:1. .

^! H NMR _{^(β-isomer) (400 MHz, CDC1 3)} : δ 8.09 (dd, J = 8.6, 1.2 Hz,

1H), 7.68 (td, J = 7.4, 1.2 Hz), 7.53 (t, J = 7.4 Hz, 2H), 6.51 (s, 1H), 5.64 (s, 2H), 4.06-4.11 (m, 1H), 3.82 (dd, J = 6.3, 2.1 Hz, 1H), 3.70-3.76 (m, 1H),

2.88 (dd, J = 6.8, 2.0 Hz, 1H), 2.67 (brs, 1H), 1.25 (d, J = 6.4 Hz, 3H), 1.18

(d, J = 6.5 Hz, 3H

Example

(1) Preparation of a compound of the formula (Hie)

Add 2,4-dichlorobenzyl alcohol (124 g), methyl 3-oxopentanoate (100 g) and toluene (300 mL) at about 20 ° C, heat to reflux, and distill off with an atmospheric distillation apparatus. Solvent to system temperature rose to 150 °C. The crude product of the obtained compound of the formula (XVIIe) was directly used in the next reaction 3 to 4 times.

The crude compound of the above formula (XVIIe), toluene (300 mL) and triethylamine (35.4 g) were added at about 20 ° C, then p-dodecylbenzenesulfonyl azide (270.4 g) was added dropwise. After the completion of the dropwise addition, the reaction was naturally returned to room temperature for 5 hours. The reaction system was concentrated to about 200 to 300 mL, then n-glycol (500 mL) was added, and the mixture was cooled and cooled in an ice water bath for about 2 hours. After filtration, the filter cake was washed with n-glycol and dried to give a compound of the formula (Hie) (158 g, yield: 75%), and the liquid phase purity was 98.9%.

^{! H NMR (400 MHz, CDC1} 3): δ 7.42 (s, 1H), 7.32-7.42 (m, 1H), 7.25-7.27 (m, 1H), 5.31 (s, 2H), 2.85 (q, J = 7.3 Hz, 2H), 1.13 (t, J = 7.3 Hz, 3H

(2) Preparation of a compound of the formula (Ie)

The compound of formula (Ille) (25.1 g) was dissolved in dichloromethane (280 mL) and cooled to

Titanium tetrachloride (13.2 g) was slowly added at -40 ° C, and the resulting yellow slurry was stirred for further 30 minutes. Triethylamine (14.1 g) was slowly added, then the reaction mixture was warmed to -20 ° C and stirring was continued for 1 hour, then a solution of 4AA (20 g) of dichloromethane (40 mL) was slowly added. After stirring at -20 °C for 3 hours, the reaction was warmed to EtOAc EtOAc. The mixture was allowed to stand for separation, and the methylene chloride phase was separated, and then concentrated to give 47.4 g of crude compound of formula (XVI).

The crude compound (47.4 g) of the compound of the formula (XVIe) was suspended in 40% aqueous acetonitrile (120 mL), and 3N HCl (40 mL) was added at 15 to 20 °C. The reaction was stirred at 15 to 20 ° C until the reaction was completed. 120 mL of ethyl acetate was added and the pH of the aqueous phase was adjusted to 6-7 with saturated sodium bicarbonate. The organic phase was separated, washed with 45 mL of brine, concentrated, and purified by silica gel chromatography to give the compound of formula (Ie) (14.1 g, two-step 49% yield) with a ratio of β/α of 10

^! H NMR _{^(β-isomer) (400 MHz, CDC1 3)} : δ 7.38 (ά, J = 2.0 Hz, 1H), 7.30 (d, J = 8.2 Hz, 1H), 7.23 (dd, J = 8.2, 2.0 Hz, 1H), 6.74 (s, 1H), 5.28 (s, 2H), 4.04-4.09 (m, 1H), 3.80 (dd, J = 6.4, 2.1 Hz, 1H), 3.69-3.75 (m, 1H ), 3.36 (brs, 1H), 2.85 (dd, J = 6.6, 1.8 Hz, 1H), 1.22 (d, J = 6.9 Hz, 3H), 1.17 (d, J = 6.9 Hz, 3H

The specific embodiments have been particularly described and described above. It is intended that the present invention is not to be construed as being limited by the scope of the disclosure.

Claims

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1. A method for preparing penem antibiotic intermediates, characterized in that it includes the following steps:

Step 1: The compound represented by chemical formula (XVI) is obtained by reacting the compound represented by chemical formula σί) and the compound represented by chemical formula σί);

Step 2: Prepare the penem antibiotic intermediate represented by the chemical formula from the compound represented by the chemical formula (XVI);

The synthetic route of the method is as follows:

II ^III Oxybenzyl; R ² represents acetyl or benzoyl;

R ³ represents trimethylsilyl or tert-butyldimethylsilyl.

2. The method according to claim 1, characterized in that the reaction of step 1 is carried out under direct Mannich reaction conditions catalyzed by Lewis acid.

3. The method according to claim 2, characterized in that the Lewis acid used for Mannich reaction is selected from titanium tetrachloride, titanium tetrabromide, silicon tetrachloride, lanthanum trichloride, zinc chloride, Zinc bromide, magnesium chloride, boron tribromide, copper chloride, copper triflate, copper triflate, copper iodide or boron trichloride, preferably titanium tetrachloride.

4. The method according to claim 3, characterized in that the molar ratio of the Lewis acid to the compound represented by the chemical formula (II) is 0.8~3.0:1, preferably 1.0~1.5:1.

5. The method according to claim 2, characterized in that a Lewis base also exists in the reaction of step 1, which is selected from the group consisting of triethylamine, diisopropylethylamine, tributylamine, tetramethylethylenediamine, 4-methylmorpholine, 1,8-diazabicyclo[5.4.0]-carbon-7-ene, 1,4-diazabicyclo[2.2.2]octane, 4-dimethylamine Pyridine, N-methylpyrrole, N-methylpiperidine, diethylamine, diisopropyl Amine, pyrrole, piperidine, hexamethylphosphoric triamide, pyridine, 3-methylpyridine or combinations thereof, with tertiary amines among them being preferred.

6. The method according to claim 5, characterized in that the molar ratio of the Lewis base and the compound represented by the chemical formula (II) is 1.2~4.0:1, preferably 1.8~2.5:1.

7. The method according to claim 2, characterized in that the reaction of step 1 is carried out in a solvent, and the solvent is selected from the group consisting of dichloromethane, 1,2-dichloroethane, toluene, acetonitrile, tetrahydrofuran, and methane. tert-butyl ether, 2-methyltetrahydrofuran or a combination thereof, preferably dichloromethane, 1,2-dichloroethane or a combination thereof; the amount of the solvent is 1 gram of the chemical formula (II) 8 to 30 mL of the compound represented by the chemical formula (II) is used, preferably 12 to 20 mL per gram of the compound represented by the chemical formula (II).

8. The method according to claim 2, characterized in that the molar ratio of the compound represented by the chemical formula (ΙΠ) and the compound represented by the chemical formula (Π) is 1.0~2.0:1, preferably 1.2~1.5:1.

9. The method according to claim 2, characterized in that the reaction temperature of step 1 is -60~10. C, preferably -30~0°C.

10. The method according to claim 2, characterized in that, after the reaction in step 1 is completed, the following quenching solution is used to quench the reaction: sodium chloride solution, sodium bicarbonate solution, sodium dihydrogen phosphate solution, potassium dihydrogen phosphate solution, magnesium chloride solution, calcium chloride solution or pure water, preferably pure water; the dosage of the quenching solution is 3 to 30 mL per gram of the compound represented by the chemical formula (II), preferably 3 to 30 mL per gram of the chemical formula (II) Use 5~10 mL of the compound shown in Π).

11. The method according to claim 1, characterized in that the reaction in step 2 is carried out under the reaction conditions of acid-catalyzed removal of trimethylsilyl or tert-butyldimethylsilyl.

12. The method according to claim 11, characterized in that the acid is selected from hydrochloric acid, sulfuric acid, methylsulfonic acid, benzenesulfonic acid or trifluoroacetic acid, preferably hydrochloric acid.

13. The method according to claim 12, characterized in that the concentration of the acid is 0.5~4 mol/L, preferably 1.0~2.0 mol/L.

14. The method according to claim 11, characterized in that the reaction of step 2 is carried out in a solvent It is carried out in a solvent selected from acetonitrile-water, methanol-water, acetone-water or tetrahydrofuran-water, preferably acetonitrile-water.

15. The method according to claim 11, characterized in that the reaction temperature of step 2 is 0~30°C, preferably 15~20°C.