CN1948281A - Imipenem intermediate and preparation method of imine peinan - Google Patents
Imipenem intermediate and preparation method of imine peinan Download PDFInfo
- Publication number
- CN1948281A CN1948281A CN 200610111831 CN200610111831A CN1948281A CN 1948281 A CN1948281 A CN 1948281A CN 200610111831 CN200610111831 CN 200610111831 CN 200610111831 A CN200610111831 A CN 200610111831A CN 1948281 A CN1948281 A CN 1948281A
- Authority
- CN
- China
- Prior art keywords
- reaction
- imipenum
- compound
- formula
- acetonitrile
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a new intermediate compound for synthesizing imipenen. Said invention also provides the chemical structure formula of said intermediate compound. Besides, said invention also provides a method for preparing imipenen side chain and imipenen.
Description
Technical field
The present invention relates to N-azomethine base sulfomycin (imipenum) in synthetic a kind of new midbody compound (I) and prepare the method for imipenum.
Background technology
Imipenum is a kind of famous microbiotic, in many patents and document, reported, and as USP4,292,436,4,374,772,2002/0095034 and Sletzinger et al., Tetrahedron Lett., 21,4221-4224 (1980).
Synthesizing imine training south has three kinds of routes at present:
(1) MERCK﹠amp; CO INC, US4292436, the 1981-09-29 route:
The advantage of this technology is that southern parent nucleus of training and the one step condensation of imines side chain form the short yield height of route.Shortcoming is that the imines side chain (VI) of protection is very unstable at air, very easily decomposes under water and the soda acid situation, or changes by following reaction structure and to be (VII).
In actually operating, can not get imines side chain (VI) substantially.
(2) MERCK ﹠amp; CO INC, US4374772, the 1983-02-22 route:
The advantage of this technology is to have avoided the synthetic difficult shortcoming that realizes of imines side chain (VI), has realized commercially producing of imipenum.Shortcoming is that synthetic route is long, the cost height, and sulfomycin (X) itself is unstable, and reaction is difficult to control.
(3) ACS DOBFAR SPA (IT), ITMI20010077D D0-2001-01-17 route:
The advantage of this technology is to have avoided sulfomycin (X) instability itself, the shortcoming that reaction is difficult to control, and technology stability improves, and cost decreases.Shortcoming is that synthetic route is long, and cost is still higher.
Summary of the invention
The object of the present invention is to provide a kind of new compound (I) of imipenum side chain preparation:
Wherein R is: carbonyl ester class
Be allyloxycarbonyl, tertbutyloxycarbonyl, carbobenzoxy-(Cbz), 4-nitro carbobenzoxy-(Cbz) etc. or silicane
-Si (CH
3)
3,-Si (CH
3)
2Et ,-Si (CH
3)
2C (CH
3)
3,-Si (CH
3)
2CH
2C
6H
5Deng-Si (R
3)
3, wherein R3 can be C
1～C
6Identical or different alkyl group, or C
7～C
12The benzene alkyl group.
These compounds process for production thereof are easy, stability high, separate easily, content and yield height, with low cost.The existing time spent can be changed (VI) easily into, thus the deficiency that has overcome prior art synthetic (VI) difficulty and decomposed easily.
The present invention also provides the preparation method of imipenum side chain, comprises the reaction of following three steps:
R-Cl can be chloro-formic ester class blocking group reagent such as allyl chlorocarbonate, chloroformic acid benzyl ester, chloroformic acid 4-nitrobenzyl ester in the first step reaction, also can be chlorosilane blocking group reagent such as trimethylchlorosilane, TERT-BUTYL DIMETHYL CHLORO SILANE; R in the iminoether salt hydrochlorate
2Can be ethyl, sec.-propyl or benzyl etc., consumption be 0.7～5 equivalent (with respect to chloro-formic esters, or chlorosilane, below all are) to the reaction of second step, preferred 1～2 equivalent; Organic bases can be pyrimidine, imidazoles, 2, preferred triethylamine such as 6-lutidine, 4-dimethylaminopyridine, triethylamine, diisopropylethylamine, diisopropylethylamine, and consumption is 1～6 equivalent, preferred 2～4 equivalents.The solvent that uses in the reaction can be dioxane, tetrahydrofuran (THF), dimethyl formamide, diisopropyl ether, methyl (or ethyl) pyrrolidone, dimethyl sulfoxide (DMSO), acetonitrile one or more, wherein preferred acetonitrile and dimethyl formamide.Temperature of reaction is 50～-78 ℃, preferred-15～-40 ℃.Be reflected under the anhydrous situation and carry out, it is clear solution (XIV) that reaction finishes the back, and this solution is directly used in the reaction of second step without processing.
Raw material (XV) is a Guang ammonia hydrochloric acid salt in the reaction of second step, consumption is 0.2～1 equivalent, preferred 0.4～0.6 equivalent, organic bases can be pyrimidine, imidazoles, 2, preferred triethylamine such as 6-lutidine, 4-dimethylaminopyridine, triethylamine, diisopropylethylamine, diisopropylethylamine, consumption is 1～3 equivalent, preferred 1～2 equivalent.The solvent that uses in the reaction can be dioxane, tetrahydrofuran (THF), dimethyl formamide, diisopropyl ether, methyl (or ethyl) pyrrolidone, dimethyl sulfoxide (DMSO), acetonitrile one or more, wherein preferred acetonitrile and dimethyl formamide.Temperature of reaction is 50～-78 ℃, preferred 10～-40 ℃.Reaction product is crystal precipitation (I).Filter, crystal washing, methyl alcohol are washed final vacuum drying, low-temperature storage.
Organic phosphine can be a trialkyl phosphine in the three-step reaction, and its alkyl can be C2～6 lower alkanes alkyl such as ethyl, propyl group, butyl.Triaryl phosphine, its aryl can be phenyl, tolyl, methoxyphenyl etc.Phosphorous acid ester, its alkyl can be C2～6 lower alkanes alkyl such as ethyl, propyl group, butyl.Preferred tributylphosphine, triphenylphosphine and triethyl-phosphite.The solvent that uses in the reaction can be dioxane, tetrahydrofuran (THF), dimethyl formamide, diisopropyl ether, methyl (or ethyl) pyrrolidone, dimethyl sulfoxide (DMSO), acetonitrile one or more, wherein preferred acetonitrile and dimethyl formamide.Also need add 1～20 normal water in the reaction, preferred 3～10 equivalents.Be reflected under the anaerobic situation and carry out, it is clear solution (VI) that reaction finishes the back, and this solution can be directly used in the condensation of next step and parent nucleus.
The present invention also provides the preparation method of imipenum, its route basically with MERCK﹠amp; CO INC is identical, but generates the side chain of imipenum with intermediate of the present invention, and technology is optimized, the purity height of reaction (VI) that obtain like this, and prepare easily, (V) yield height of generation, purity is also high,
In the formula: R
1For
X is-OPO (Oph)
2
In the present invention, each abbreviation is expressed as follows: Et: ethyl; PNZ: to the nitro carbobenzoxy-(Cbz); PNB: p-nitrophenyl methyl; Ph: phenyl; Boc: tertbutyloxycarbonyl; Tms: trimethyl silicon based; Tbdms: tertiary butyl dimethyl is silica-based.
Embodiment
The test materials that the present invention is used if no special instructions, is commercially available purchase product.
[embodiment 1] N, N '-two [(N-is to the nitro carbobenzoxy-(Cbz)) imines methylene base] cystamine N, N '-Di (N-p-nitrobenzyloxycarbonyl) formimidoyl) preparation of cystamine:
Under argon (or nitrogen) gas shiled, add the imido benzyl oxide hydrochloride of 51.5g (0.30mol) and the acetonitrile of 100ml and form suspension.Dry ice-ethanol bath cools to below-40 ℃ reaction solution, stir and add 73.0g (98ml down, 0.565mol) diisopropylethylamine, be dissolved in the solution of 50ml acetonitrile then at the nitrobenzyl chloroformate ester that under uniform temp, adds 51.2g (0.238mol), stir 20min, the limpid solution that obtains is reaction solution A for containing the solution of N-(to the nitro carbobenzoxy-(Cbz))-imines benzyl formate (Benzyl (N-p-nitrobenzyloxycarbonyl) formimidate).
In the single port bottle of a 250ml, add 2-aminoethyl disulfide dihydrochloride 26.7g (0.119mol), add pyrrolidone and 31g (0.238mol) the diisopropylethylamine concussion dissolving of 100ml then.The reaction mixture that obtains is reaction solution B.After reaction solution B is cooled to 0 ℃, pour in the dropping funnel, be added drop-wise to (temperature of reaction remains on-40～-20 ℃) among the reaction solution A, stirring reaction then had a large amount of throw outs to generate ,-10 ℃ of following stirring reactions 1 hour.Filter, filter cake washs 40 ℃ of vacuum-dryings, P with the water of 300ml and the ethyl acetate making beating of 300ml respectively
2O
5Help driedly, obtain N, N '-two [(N-is to the nitro carbobenzoxy-(Cbz)) imines methylene base] cystamine [N, N '-Di ((N-p-nitrobenzyloxycarbonyl) formimidoyl) cystamine] 57g (yield 85%, content 96%).
Mp：113～115℃
The determination of physical appearance result of compound:
Ms：M+1＝565
IR
max neat(cm
-1)：1702，1642?1606，1520，1443，1344，1246，1175，854
1H-NMR (δ, DMSO-d
6): 2.91 (4H, m, SCH
2), 3.58 (4H, m, NCH
2), 5.18 (4H, s, OCH
2), 7.60 and 8.20 (8H, m, ArH), 8.39 (2H, d, NCH=N).
13C-NMR(ppm，DMSO-d
6)：36.3(SCH
2)，39.1(NCH
2)，65.3(OCH
2)，123.9(Ar-C
3，5)，128.7(Ar-C
2，6)，145.5(Ar-C
1)，147.3(Ar-C
4)，161.5(NCH＝N)，164.0(NCO
2).
[embodiment 2] N, N '-two [(N-carbobenzoxy-(Cbz)) imines methylene base] cystamine N, the preparation of N '-Di ((N-benzyloxycarbonyl) formimidoyl) cystamine:
The solution that the nitrobenzyl chloroformate ester of adding 51.2g (0.238mol) in embodiment 1 is dissolved in the 50ml acetonitrile is dissolved in the solution of 50ml acetonitrile instead of the chloroformic acid benzyl ester of 40.6g (0.238mol), and other dosages are all identical with method.Obtain N, N '-two [(N-carbobenzoxy-(Cbz)) imines methylene base] cystamine [N, N '-Di ((N-benzyloxycarbonyl) formimidoyl) cystamine] 33.9g (yield 60%, content 96%).
Mp：120～122℃
The determination of physical appearance result of compound:
Ms：M+1＝475
IR
max KBrcm
-1：1739，1699，1675，1639，1447，1241，1168，761.
1H-NMR(δ，DMSO-d
6)：2.89(4H，m，SCH
2)，3.55(4H，m，NCH
2)，5.05(4H，s，OCH
2)，7.34(10H，m，ArH)，8.38(2H，d，NCH＝N).
13C-NMR(ppm，DMSO-d
6)：36.3(SCH
2)，39.1(NCH
2)，66.5(OCH
2)，128.2～128.8(Ar-C
2，3，5，6)，137.5(Ar-C
1，4)，161.2(NCH＝N)，164.2(NCO
2).
[embodiment 3] N, N '-two [(N-allyloxycarbonyl) imines methylene base] cystamine N, the preparation of N '-Di ((N-allyloxycarbonyl) formimidoyl) cystamine:
The solution that the nitrobenzyl chloroformate ester of adding 51.2g (0.238mol) in embodiment 1 is dissolved in the 50ml acetonitrile is dissolved in the solution of 50ml acetonitrile instead of the allyl chlorocarbonate of 28.7g (0.238mol), and other dosages are all identical with method.Obtain N, N '-two [(N-allyloxycarbonyl) imines methylene base] cystamine [N, N '-Di ((N-allyloxycarbonyl) formimidoyl) cystamine] 33.4g (yield 75%, content 95%).
Mp：108～110℃
The determination of physical appearance result of compound:
Ms：M+1＝375
IR
max KBrcm
-1：1698，1640，1449，1336，1241，1178，1085，983，794.
1H-NMR(δ，DMSO-d
6)：2.91(4H，m，SCH
2)，3.53(4H，m，NCH
2)，4.50(4H，d，OCH
2)，5.23(4H，m，＝CH
2)，5.91(2H，m，-CH＝)，8.35(2H，d，NCH＝N).
13C-NMR(ppm，DMSO-d
6)：36.4(SCH
2)，39.4(NCH
2)，65.5(OCH
2)，117.6(＝CH
2)，134.0(-CH＝)，161.2(NCH＝N)，164.0(NCO
2).
[embodiment 4] N, N '-two [(N-tertbutyloxycarbonyl) imines methylene base] cystamine N, the preparation of N '-Di ((N-tert-butyloxycarbonyl) forimidoyl) cystamine:
The solution that the nitrobenzyl chloroformate ester of adding 51.2g (0.238mol) in embodiment 1 is dissolved in the 50ml acetonitrile is dissolved in the solution of 50ml acetonitrile instead of the tert-Butyl dicarbonate of 51.9g (0.238mol), and other dosages are all identical with method.Obtain N, N '-two [(N-tertbutyloxycarbonyl) imines methylene base] cystamine [N, N '-Di ((N-tert-butyloxycarbonyl) forimidoyl) cystamine] 41.1g (yield 85% content 95%).
Mp：108～110℃
The determination of physical appearance result of compound:
Ms：M+1＝407
IR
max KBr?cm
-1：2960，2870，1698，1640，1460，1449，1380，1336，1241?1178，1085，983，794.
1H-NMR(δ，DMSO-d
6)：1.40(18H，s，CCH
3)，2.89(4H，m，SCH
2)，3.55(4H，m，NCH
2)，8.3?8(2H，d，NCH＝N).
13C-NMR(ppm，DMSO-d
6)：28.5(CH
3)，36.4(SCH
2)，39.4(NCH
2)，83.2(O-C-)，161.2(NCH＝N)，164.0(NCO
2).
[embodiment 5] N, N '-two [(N-is trimethyl silicon based) imines methylene base] cystamine N, the preparation of N '-Di ((N-trimethylsilyl) formimidoyl) cystamine:
The solution that the nitrobenzyl chloroformate ester of adding 51.2g (0.238mol) in embodiment 1 is dissolved in the 50ml acetonitrile is dissolved in the solution of 50ml acetonitrile instead of the trimethylchlorosilane of 25.9g (0.238mol), and other dosages are all identical with method.Use chloroform/acetone (3: 1v/v) cross silicagel column at last for elutriant, obtain N, N '-two [(N-is trimethyl silicon based) imines methylene base] cystamine [N, N '-Di ((N-trimethylsilyl) formimidoyl) cystamine] 14.6g (yield 35%, content 95%) single component oily matter.
The determination of physical appearance result of compound:
Ms：M+1＝351
IR
max KBr?cm
-1：2960，2870，1698，1640，1460，1449，1380.
1H-NMR(δ，DMSO-d
6)：0.08(18H，s，Si(CH
3)
3)，2.89(4H，m，SCH
2)，3.20(4H，m，NCH
2)，8.38(2H，d，NCH＝N).
13C-NMR(ppm，DMSO-d
6)：1.0(CH
3)，36.4(SCH
2)，39.4(NCH
2)，161.2(NCH＝N).
[embodiment 6] N, N '-two [(N-tertiary butyl dimethyl is silica-based) imines methylene base] cystamine N, the preparation of N '-Di ((N-tert-butyldimethylsilyl) formimidoyl) cystamine:
The solution that the nitrobenzyl chloroformate ester of adding 51.2g (0.238mol) in embodiment 1 is dissolved in the 50ml acetonitrile is dissolved in the solution of 50ml acetonitrile instead of the dimethyl tertiary butyl chloride silane of 36.0g (0.238mol), and other dosages are all identical with method.Use chloroform/acetone (3: 1v/v) cross silicagel column at last for elutriant, obtain N, N '-two [(N-tertiary butyl dimethyl is silica-based) imines methylene base] cystamine [N, N '-Di ((N-tert-butyldimethylsilyl) formimidoyl) cystamine] 28.5g (yield 55%, content 96%) single component oily matter.
The determination of physical appearance result of compound:
Ms：M+1＝436
IR
max KBr?cm
-1：2960，2870，1698，1640，1460，1380.
1H-NMR(δ，DMSO-d
6)：0.08(12H，s，Si(CH
3)
2)，1.00(18H，s，C(CH
3)
3)，2.89(4H，m，SCH
2)，3.20(4H，m，NCH
2)，8.38(2H，d，NCH＝N).
13C-NMR(ppm，DMSO-d
6)：-6.5(Si(CH
3)
2)，27.1(C(CH
3)
3)，36.4(SCH
2)，39.4(NCH
2)，161.2(NCH＝N).
Synthesizing of [embodiment 7] double protection imipenem
1, alkene phosphide (IV) is synthetic:
Under argon (nitrogen) gas shiled, add the anhydrous acetonitrile of 20.0g (57.4mmol) dicyclo ketone ester (III) and 100ml.System is cooled to about-15 ℃.(11.0ml, 63.1mmol), reaction system becomes red-brown, adds DPC 15.4g (57.4mmol) then to add DIPEA 8.2g under stirring below-15 ℃.Stirring reaction is 1 hour under uniform temp, and reaction finishes.Mixture is the solution of alkene phosphide (IV).Be kept at-10 ℃ stand-by (for reaction A liquid).
2, imines side chain (VI) is synthetic:
Get 250ml single port flask.Add 17.8g (31.6mmol) N; N '-two [(N-is to the nitro carbobenzoxy-(Cbz)) imines methylene base] cystamine [N; N '-Di ((N-p-nitrobenzyloxycarbonyl) formimidoyl) cystamine] (I) and the acetonitrile of 100ml form suspension; reenter and add 3.5ml water; the TnBP that under argon (or nitrogen) gas shiled, adds 7.0g (34.4mmol); sealed flask; stirred 45 minutes; white solid dissolves fully; reaction finishes, and mixture is that N-[(N-is to the nitro carbobenzoxy-(Cbz)) imines methylene base] (VI) solution of amido ethanethio [N-((N-p-nitrobenzyloxycarbonyl) formimidoyl) aminoethylthiol].Need not any processing be used for the next step use (for reaction B liquid).
3, double protection imipenem (V) is synthetic:
To react A liquid and under argon (or nitrogen) gas shiled, reaction solution be cooled to below-10 ℃ with dry ice-ethanol bath, and adding DIPEA8.2g under stirring (11.0ml, 63.1mmol).To react B liquid again changes in the dropping funnel of 200ml under argon (or nitrogen) gas shiled.30min will react B liquid and join in the reaction A liquid under uniform temp; temperature is raised to 10 ℃ then, stirs 1 hour, is the faint yellow mixture that crystallisate is arranged; under 0～10 ℃ of stirring, drip the water of 2000ml; stirred 30 minutes, and filtered and obtain thick double protection imipenem, use the water of 3 * 30ml then respectively; the methyl alcohol of 30ml and the methyl tertiary butyl ether of 50ml making beating cleaning product; drain, obtain the double protection imipenem (V) of 28g (yield 79.5%, purity 94%) after the vacuum-drying.
Mp：116～118℃
The determination of physical appearance result of compound:
Ms：M+1＝614
IR
max KBr?cm
-1：
1H-NMR (δ, DMSO-d
6): 1.10 (3H, s, CH
3), 3.07 (2H, s, SCH
2), 3.16 (1H, s, 6-H), 3.52 (2H, s, 4-H), 3.94 (2H, s, NCH
2), 4.16 (2H, s, 8-H, 5-H), 5.18-5.41 (4H, m, OCH
2), 7.60,7.68,8.21 and 8.32 (8H, m, ArH), 8.41 (2H, d, NCH=N).
13C-NMR(ppm，DMSO-d
6)：22.1(C9)，30.5(SCH
2)，39.3(NCH
2)，41.2(C4)，52.3(C5)，64.2，64.9(2×OCH
2)，65.5，66.8(C6，C8)，122.8(C2)，124.0(2×ArC
3，5)，128.6，128.7(2×ArC
2，6)，144.5，145.6(2×Ar-C
1)，147.3，147.5(2×Ar-C
4)，150.9(C3)，160.8(COOR)，161.6(NCH＝N)，164.0(NCO
2)，177.9(C7).
More than the description of better embodiment of the present invention is not limited the present invention, those skilled in the art can make various changes or distortion according to the present invention, only otherwise break away from spirit of the present invention, all should belong to the scope of claims of the present invention.
Claims (11)
1, a kind of imipenum intermediate has suc as formula structure shown in (I):
Wherein R is the carbonyl ester class that is shown below:
Be allyloxycarbonyl, tertbutyloxycarbonyl, carbobenzoxy-(Cbz), 4-nitro carbobenzoxy-(Cbz);
Or as shown in the formula silicane:
-Si (CH
3)
3,-Si (CH
3)
2Et ,-Si (CH
3)
2C (CH
3)
3,-Si (CH
3)
2CH
2C
6H
5,-Si (R
3)
3, wherein R3 is C
1～C
6Identical or different alkyl group, or be C
7～C
12The benzene alkyl group.
2, the described imipenum intermediate of claim 1 is characterized in that described R is to nitro Bian oxygen carbonyl, has the structure of being shown below:
3, the described imipenum intermediate of claim 1 is characterized in that described R is a Bian oxygen carbonyl, has the structure of being shown below:
4, the described imipenum intermediate of claim 1 is characterized in that described R is an allyloxycarbonyl, has the structure of being shown below:
5, the described imipenum intermediate of claim 1 is characterized in that described R is a tertbutyloxycarbonyl, has the structure of being shown below:
6, the described imipenum intermediate of claim 1 is characterized in that described R is trimethyl silicon based, has the structure of being shown below:
7, the described imipenum intermediate of claim 1 is characterized in that described R is that tertiary butyl dimethyl is silica-based, has the structure of being shown below:
8, a kind of method for preparing the imipenum side chain comprises the steps:
1) R-Cl and formula (XI) compound are reacted production (XIV) compound in the presence of organic bases;
2) formula (XIV) compound and formula (XV) compound are reacted production (I) compound, i.e. imipenum intermediate in the presence of organic bases;
3) in the presence of organic phosphine, change formula (I) compound into formula (VI) compound, i.e. imipenum side chain;
Reaction scheme is as follows:
Wherein, R-Cl is chloro-formic ester class blocking group reagent or chlorosilane blocking group reagent;
R is the carbonyl ester class that is shown below:
Be allyloxycarbonyl, tertbutyloxycarbonyl, carbobenzoxy-(Cbz), 4-nitro carbobenzoxy-(Cbz);
Or as shown in the formula silicane:
-Si (CH
3)
3,-Si (CH
3)
2Et ,-Si (CH
3)
2C (CH
3)
3,-Si (CH
3)
2CH
2C
6H
5,-Si (R
3)
3, wherein R3 is C
1～C
6Identical or different alkyl group, or be C
7～C
12The benzene alkyl group;
R
2Be ethyl, sec.-propyl or benzyl.
9, the described method for preparing the imipenum side chain of claim 8, wherein
R-Cl is the chloro-formic ester class blocking group reagent of allyl chlorocarbonate, chloroformic acid benzyl ester, chloroformic acid 4-nitrobenzyl ester in the described step 1), or is the chlorosilane blocking group reagent of trimethylchlorosilane, TERT-BUTYL DIMETHYL CHLORO SILANE; R
2Be ethyl, sec.-propyl or benzyl, consumption is 0.7～5 equivalent with respect to the amount of chloro-formic ester or chlorosilane; Described organic bases is selected from pyrimidine, imidazoles, 2,6-lutidine, 4-dimethylaminopyridine, triethylamine and diisopropylethylamine; The solvent that uses in the reaction is selected from one or more of dioxane, tetrahydrofuran (THF), dimethyl formamide, diisopropyl ether, methyl (or ethyl) pyrrolidone, dimethyl sulfoxide (DMSO) and acetonitrile;
Described step 2) Chinese style (XV) compound is a Guang ammonia hydrochloric acid salt, consumption is 0.2～1 equivalent with respect to the amount of chloro-formic ester or chlorosilane, organic bases is selected from pyrimidine, imidazoles, 2,6-lutidine, 4-dimethylaminopyridine, triethylamine and diisopropylethylamine, consumption are 1～3 equivalent with respect to the amount of chloro-formic ester or chlorosilane; The solvent that uses in the reaction is selected from one or more of dioxane, tetrahydrofuran (THF), dimethyl formamide, diisopropyl ether, methyl (or ethyl) pyrrolidone, dimethyl sulfoxide (DMSO) and acetonitrile, and temperature of reaction is 50～-78 ℃;
Organic phosphine is a trialkyl phosphine in the described step 3), and wherein alkyl is C
2～C
6Lower alkanes alkyl, or triaryl phosphine, wherein aryl is phenyl, tolyl or methoxyphenyl, or phosphorous acid ester, wherein alkyl is C
2～C
6The lower alkanes alkyl; The solvent that uses in the reaction is selected from one or more of dioxane, tetrahydrofuran (THF), dimethyl formamide, diisopropyl ether, methyl or ethyl pyrrolidone, dimethyl sulfoxide (DMSO) and acetonitrile, add 1～20 normal water in the reaction, be reflected under the oxygen free condition and carry out.
10, the described method for preparing the imipenum side chain of claim 9, wherein
R in the described step 1)
2Consumption is 1～2 equivalent; Organic bases is triethylamine or diisopropylethylamine, and consumption is 2～4 equivalents; The solvent that uses in the reaction is acetonitrile and dimethyl formamide, and temperature of reaction is-15～-40 ℃; Reaction finishes back solution and is directly used in the reaction of second step without processing;
Described step 2) consumption of Chinese style (XV) compound is 0.4～0.6 equivalent, organic bases is triethylamine or diisopropylethylamine, and consumption is 1～2 equivalent, and the solvent that uses in the reaction is acetonitrile and dimethyl formamide, temperature of reaction is 10～-40 ℃, and reaction product is crystal precipitation (I);
Organic phosphine is tributylphosphine, triphenylphosphine or triethyl-phosphite in the described step 3), and the solvent that uses in the reaction is acetonitrile and dimethyl formamide, adds 3～10 normal water in the reaction.
11, the preparation method of imipenum comprises the steps:
1) in the presence of organic phosphine, changes formula (I) compound into formula (VI) compound, i.e. imipenum side chain;
2) imipenum parent nucleus formula (IV) compound and formula (VI) compound are carried out condensation reaction and obtain formula V compound, i.e. double protection imipenem;
3) formula V compound deprotection base is obtained imipenum;
Reaction scheme is as follows:
Wherein R is the carbonyl ester class that is shown below:
Be allyloxycarbonyl, tertbutyloxycarbonyl, carbobenzoxy-(Cbz), 4-nitro carbobenzoxy-(Cbz);
Or as shown in the formula silicane:
-Si (CH
3)
3,-Si (CH
3)
2Et ,-Si (CH
3)
2C (CH
3)
3,-Si (CH
3)
2CH
2C
6H
5,-Si (R
3)
3, wherein R3 is C
1～C
6Identical or different alkyl group, or be C
7～C
12The benzene alkyl group;
R
1For
X is-OPO (Oph)
2
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2006101118311A CN100424071C (en) | 2006-07-05 | 2006-08-25 | Imipenem intermediate and preparation method of imine peinan |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200610090209 | 2006-07-05 | ||
| CN200610090209.7 | 2006-07-05 | ||
| CNB2006101118311A CN100424071C (en) | 2006-07-05 | 2006-08-25 | Imipenem intermediate and preparation method of imine peinan |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1948281A true CN1948281A (en) | 2007-04-18 |
| CN100424071C CN100424071C (en) | 2008-10-08 |
Family
ID=38017924
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2006101118311A Expired - Fee Related CN100424071C (en) | 2006-07-05 | 2006-08-25 | Imipenem intermediate and preparation method of imine peinan |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN100424071C (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008006302A1 (en) * | 2006-07-05 | 2008-01-17 | Shanghai Buddy Bio-Pharm Intermediates Ltd | An intermediate of imipenem and a method for prearing imipenem |
| CN101747334B (en) * | 2008-12-16 | 2012-08-08 | 上海医药工业研究院 | Method for preparing double protection imipenem |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4292436A (en) * | 1980-06-25 | 1981-09-29 | Merck & Co., Inc. | Process for the preparation of N-protected N-formimidoyl 2-aminoethanethiol |
-
2006
- 2006-08-25 CN CNB2006101118311A patent/CN100424071C/en not_active Expired - Fee Related
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008006302A1 (en) * | 2006-07-05 | 2008-01-17 | Shanghai Buddy Bio-Pharm Intermediates Ltd | An intermediate of imipenem and a method for prearing imipenem |
| CN101747334B (en) * | 2008-12-16 | 2012-08-08 | 上海医药工业研究院 | Method for preparing double protection imipenem |
Also Published As
| Publication number | Publication date |
|---|---|
| CN100424071C (en) | 2008-10-08 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1035555C (en) | Processes for diastereoselective synthesis of nucleosides | |
| AU678423B2 (en) | 2-debenzoyl-2-acyl taxol derivatives and methods for making same | |
| CN1948312A (en) | Preparation method of meluopeinan | |
| WO2007004028A2 (en) | Processes for the preparation of penems and its intermediate | |
| CN1870998A (en) | CCR-2 antagonist salt | |
| CN1628118A (en) | Process for prepn. of cefdinir | |
| CN1294132C (en) | Synthesis of temozolomide and analogs | |
| CN102351802B (en) | Method for synthesizing N-monosubstituted piperazine-2,3-dione | |
| CN101031574A (en) | New diamine salt of cephalosporins and its preparation | |
| CN1948281A (en) | Imipenem intermediate and preparation method of imine peinan | |
| CN1033521A (en) | Novel 2-guanidine radicals thiazolium compounds and preparation method thereof, and the intermediate that is used as Famotidine pyridine preparation technology | |
| CN1308319C (en) | Process for synthesis of HTV protease inhibitors | |
| CN110551144B (en) | Preparation method of amoxicillin | |
| CN1155593C (en) | Process for reaction of CO2 on heterocyclic compound under co-catalysis of transistion metal complex and organic alkali | |
| CN1247562C (en) | Method for production of spirocyclic tetronic acid derivatives | |
| CN111170893A (en) | Lefamulin intermediate compound and application thereof in preparation of Lefamulin | |
| CN1227240C (en) | Process for producing 2-alkyl-4-isothiazoline-3-one | |
| CN105636933B (en) | The method for preparing the intermediate of Iopromide | |
| CN1846696A (en) | Method for producing enantiomer-free n-methyl-n- [(1s)-1-phenyl- 2-((3s)- 3-hydroxypyrrolidine- 1-yl)ethyl]- 2,2-diphenyl acetamide | |
| CN1190429C (en) | Method for producing 2-chloro-5-chloromethyl-1,3-thiazole | |
| CN102432616B (en) | Method for preparing L-prolinamide and intermediate thereof | |
| CN1930116A (en) | Chiral tertiary aminoalkylnaphthols | |
| CN1116294C (en) | Synthesis of 3-carbomethoxy-4,5-dimethylthiophene | |
| CN1887886A (en) | Prepn of carbapenum type antibiotic Faropenum sodium | |
| CN1268950A (en) | Method for preparing oxazaphosphorin-2-amines |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| ASS | Succession or assignment of patent right |
Owner name: ANHUI BUDDY BIO-PHARM INTERMEDIATES LTD. Free format text: FORMER OWNER: SHANGHAI BADI BIOMEDICINE SCIENCE AND TECHNOLOGY CO., LTD. Effective date: 20100901 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| COR | Change of bibliographic data |
Free format text: CORRECT: ADDRESS; FROM: 200072 ROOM 402, NO.2, LANE 750, LUOCHUAN MIDDLE ROAD, SHANGHAI TO: 235000 LEIHE ROAD, XINCAI INDUSTRIAL PARK, LIESHAN DISTRICT, HUAIBEI CITY, ANHUI PROVINCE |
|
| TR01 | Transfer of patent right |
Effective date of registration: 20100901 Address after: 235000 Xincai Industrial Park in Anhui province Huaibei city Lieshan District Thunder Road Patentee after: Anhui Bardi biological medicine science and Technology Co Ltd Address before: 200072 room 2, Lane 750, 402 Middle Road, Shanghai, Luochuan Patentee before: Shanghai Buddy Bio-pharm Intermediates Ltd. |
|
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20081008 Termination date: 20140825 |
|
| EXPY | Termination of patent right or utility model |