CN106146545A - A kind of preparation method of antibiotic medicine intermediate - Google Patents
A kind of preparation method of antibiotic medicine intermediate Download PDFInfo
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- CN106146545A CN106146545A CN201610397652.2A CN201610397652A CN106146545A CN 106146545 A CN106146545 A CN 106146545A CN 201610397652 A CN201610397652 A CN 201610397652A CN 106146545 A CN106146545 A CN 106146545A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
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Abstract
The invention discloses the preparation method of a kind of antibiotic medicine intermediate, including: compound A and compound 2S AM2, in the presence of metallic catalyst, reacts in organic solvent A, and reaction terminates, and post processing obtains compound A-28.The invention provides the preparation method of a kind of brand-new antibiotic medicine intermediate A 8, use the initiation material that price is cheap, and whole yield is higher, the method itself need not the process conditions of harshness simultaneously, is suitable to industrialized production, has huge market-oriented prospect.
Description
Technical field
The present invention relates to the preparation field of pharmaceutical intermediate；It is specifically related to the preparation side of a kind of antibiotic medicine intermediate
Method.
Background technology
Antibiotic is previously referred to as antibiotics, and in fact it can not only kill antibacterial and former to mycete, mycoplasma, clothing
Other pathogenic microorganism such as body, spirillum, rickettsia also have good suppression and killing action, are generally renamed as by antibiotics
For antibiotic.Antibiotic can be a kind of material produced during certain micro-organisms growth and breeding, for the antibiotic cured the disease
In addition to thus extracting directly；Also have the most completely with synthetic or part synthetic.Generally, antibiotic is used for controlling exactly
Treat the medicine of various Non-viral infections.But in Clinical practice, manifested many side effect.
Antibiotic by antibacterial, mycete or other microorganism in life process produced by have antipathogen different
Antibiotic medicine or a class material of other activity.Since nineteen forty-three, penicillin is applied to clinic, and the kind of existing antibiotic is
Reach thousand of kinds.That commonly uses clinically also has hundreds of kind.It is mainly from the culture fluid of microorganism extract or with synthesize,
Semisynthesis manufactures.
Antibiotic medicine midbody compound A8 be synthesis beta-Lactam antibiotic important intermediate, its structural formula is such as
Shown in lower:
In structural formula, R represents trimethyl silica-based (A8-1) or t-Butyldimethylsilyl (A8-2)；
The commonly used following route of the current industrialized production of this compound:
This route, with compound 4-AA as initiation material, obtains compound I, compound I through spirocyclization and is hydrolyzed into chemical combination again
Thing 4-BMA, compound 4-BMA and magnesium salt reacting generating compound II, last and reaction of sodium azide generates midbody compound
A8.This reaction scheme is full of twists and turns, and step is long, and total recovery is on the low side, and volution thing and carbonyl dimidazoles utilization rate are low, though practical
But uneconomical, the preparation cost causing midbody compound A8 is the highest.
Summary of the invention
For solving uneconomic problem of existing reaction scheme, the present invention provides one not only to have shorter synthesis step,
And preparation cost is low, the preparation method of the antibiotics intermediate of great commercial value.
A kind of preparation method of antibiotic medicine intermediate, including:
Compound A and compound 2S-AM2, in the presence of metallic catalyst, reacts in organic solvent A, and reaction terminates, after
Process obtains compound A-28；The structure of described compound A is as follows:
In above formula, R represents hydrogen or trimethyl is silica-based or t-Butyldimethylsilyl；More preferably trimethyl silica-based or
T-Butyldimethylsilyl；
The structure of described compound 2S-AM2 is as follows:
In above formula, X represents F (fluorine) or Cl (chlorine) or Br (bromine) or I (iodine)；More preferably Cl (chlorine) or Br (bromine)；
The structure of described compound A-28 is shown below:
In above formula, R represents hydrogen or trimethyl is silica-based or t-Butyldimethylsilyl；More preferably trimethyl is silica-based
Or t-Butyldimethylsilyl (A8-2) (A8-1)；
The course of reaction of the present invention is as follows:
As preferably, concrete steps include:
(I) compound A is dissolved in organic solvent A, adds metal, after temperature reaction completely, cooling；
(II) it is added dropwise to compound 2S-AM2 again and is dissolved in the solution of organic solvent A, after reaction terminates, be filtered to remove insoluble
Thing；
(III), after feed liquid desolvation, organic solvent B stirring is added molten clearly；
(IV) dilute acid soln washing is added, then with aqueous salt solu-tion to neutral；
(V) the organic facies desolvation after washing, to the most dry, add organic solvent C stirred crystallization, more by centrifugation, dries
After compound A-28.
For above-mentioned two technical scheme:
As preferably, described metal is (1.0～3.0) with the mol ratio of compound A: 1；As further preferably, described
The mol ratio of metal and compound A be (1.0～1.5): 1, as further preferred, described metal and compound A mole
Than being (1.2～1.5): 1.The described metal one or both mixture in zinc, magnesium；As further preferably, described
Metal is zinc.
As preferably, the mol ratio of described compound 2S-AM2 and compound A is (1.0～2.0): 1；As the most excellent
Choosing, the mol ratio of described compound 2S-AM2 and compound A is (1.0～1.5): 1.As further preferred, described chemical combination
The mol ratio of thing 2S-AM2 and compound A is (1.1～1.5): 1.
As preferably, described compound 2S-AM2 is the one during X-C key is left-handed, dextrorotation, racemization in structural formula or appoints
Anticipate multiple mixture.
As preferably, described organic solvent A be oxolane, 2 upper for the oxolane of C1～C4 alkyl, on 3 be
A kind of or the most multiple mixture in the oxolane of C1～C4 alkyl, 1,4-dioxane.As further preferably, walk
Suddenly, in (I), described organic solvent A is one or both the mixture in oxolane, 2-methyltetrahydrofuran.As more entering
One step is preferred, and described organic solvent A is oxolane.As preferably, the consumption of organic solvent A is the 0.5-of compound 4-AA
20 times (V/W), as further preferably, the consumption of organic solvent A is 0.5-20 times (L/Kg) of compound 4-AA, as more entering
One step is preferred, and described organic solvent A is (1.5～5) with the envelope-bulk to weight ratio of compound 4-AA: 1 (L/Kg).
In step (I), as preferably, reaction temperature is-10 DEG C of stable reflux temperatures to organic solvent A.As preferably,
After this step reaction is complete, the temperature of cooling is-20～40 DEG C；More preferably 0～10 DEG C.
In step (II), as preferably, the consumption of organic solvent A is 0.5-30 times (V/W) of compound 2S-AM2；As
Further preferably, the consumption of organic solvent A is 0.5-30 times (L/Kg) of compound 2S-AM2.More preferably 3～5 times
(L/Kg)。
In step (II), as preferably, reaction temperature is 0～30 DEG C, and the response time is 1～8 hour；As the most excellent
Choosing, reaction temperature is 0～5 DEG C, and the response time is 3～5 hours.
In step (III), as preferably, the mode of precipitation be decompression, conventional in one or both hybrid mode.Excellent
Elect decompression as.
In step (III), as preferably, organic solvent B be dichloromethane, chloroform, carbon tetrachloride, dichloroethanes,
A kind of or the most multiple mixture in ethyl acetate, toluene, benzene；As further preferably, described organic solvent B is two
One or both mixture in chloromethanes, chloroform.Further it is preferably dichloromethane.As preferably, this step
The consumption of middle organic solvent B is 0.5-30 times (V/W) of compound 4-AA；As further preferably, the consumption of organic solvent B is
0.5-30 times (L/Kg) of compound 4-AA；As further preferred, organic solvent B and the envelope-bulk to weight ratio of compound 4-AA
For (3～10): 1 (L/Kg).
In step (III), as preferably, molten clear temperature is 0～50 DEG C, preferably 20～25 DEG C.
In step (IV), as preferably, described acid is hydrochloric acid, sulphuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, C1～C5
Carboxylic acid in a kind of or the most multiple mixture, or its aqueous solution, preferably hydrochloric acid or aqueous hydrochloric acid solution.When adding water
During solution, the mass fraction of acid solution is 0.1%～20%, preferably 3%～5%.The consumption of diluted acid is organic solvent B
0.1～20 times (V/V), as further preferably, the consumption of diluted acid is 3～5 times (V/V) of organic solvent B.Described weak acid scrubbing
Number of times be 1～10 time, preferably 1～3 time.Described saline is a kind of or the most multiple mixing in sodium salt, potassium salt, ammonium salt
The aqueous solution of thing, preferably sodium-chloride water solution.The mass fraction of described saline is 0.1%～20%, preferably 5%～8%.
The consumption of described saline is 0.1～20 times (V/V) of organic solvent B, preferably 3～5 times.The number of times of described saline washing is
It is washed till till organic facies is neutrality.
In step (V), the mode of precipitation be decompression, conventional in one or both hybrid mode, be preferably decompression.
In step (V), organic solvent C is a kind of or the most multiple mixture in the alkane of C5～C10, ether.Make
For further preferably, organic solvent C is one or both mixture in hexamethylene, normal hexane.The consumption of described organic solvent C
0.5-30 times (V/W) for compound 4-AA；As further preferably, the consumption of described organic solvent C is compound 4-AA's
0.5-30 times (L/Kg), as further preferred, the envelope-bulk to weight ratio of described organic solvent C and compound 4-AA be (3～
10): 1 (L/Kg).Crystallization temperature is-20～50 DEG C, preferably 20～25 DEG C.Baking material temperature is 5～100 DEG C, preferably 30～
50℃。
The present inventor lasting for years prepare compound A-28 during, through constantly research, develop
One not only has a shorter synthesis step, and the synthetic route of great commercial value.The technology contents of the present invention is the most still
Have no that document is reported.
The compound 2S-AM2 used in the present invention can be prepared by following method:
Concretely comprise the following steps: just Hydrazoic acid,sodium salt and alkali is dissolved in water and obtains solution A.By 4-halo-3-oxo-pentanoic acid (4-nitro
Benzene) methyl ester is dissolved in acetone, temperature control dropping solution A；Temperature control dropping mesyl chloride, drips Bi Fanying complete.Reaction is rear place after terminating
Manage 4-chloro-2-diazonium-3-oxo-pentanoic acid (4-Nitrobenzol) methyl ester, 4-halo (F or Cl or Br or I)-2-diazonium-3-oxo-
Valeric acid (4-Nitrobenzol) methyl ester.
Wherein 4-halo-3-oxo-pentanoic acid (4-Nitrobenzol) methyl ester can be selected for commercially available prod, or makes by the following method
For obtaining:
Particularly as follows: 2-halogenated acetic acids and N, N-carbonyl dimidazoles reacts in organic solvent；After reaction completely, be cooled to-
20～30 DEG C, add magnesium chloride and malonic acid single pair of p-Nitrobenzyl reacts；React post processing and obtain 4-halo-3-oxygen
Generation-valeric acid (4-Nitrobenzol) methyl ester.
Compared with prior art, beneficial effects of the present invention is embodied in:
The invention provides the preparation method of a kind of brand-new antibiotic medicine intermediate A 8, use cheap the initiateing of price
Raw material, and whole yield is higher, the method itself need not the process conditions of harshness simultaneously, is suitable to industrialized production, has huge
Big market-oriented prospect.
Detailed description of the invention
In order to make technical scheme and advantage clearer, below the preferred embodiments of the present invention is made into one
The detailed description of step, the present invention includes but not limited to following example.
Embodiment 1:
The preparation of 4-chloro-3-oxo-pentanoic acid (4-Nitrobenzol) methyl ester:
108.5kg 2-chloropropionic acid is dissolved in 550L dichloromethane, adds 165kg N, N '-carbonyl dimidazoles, temperature control
18-20 DEG C of reaction 1h.After reaction completely, it is cooled to 0 DEG C, is sequentially added into 100kg magnesium chloride and 239kg malonic acid single pair of nitrobenzyl
Ester, reacts 15min in 0 DEG C, then is warming up to back flow reaction 2h.After reaction terminates, adding mass fraction is the hydrochloric acid of 10%, adjusts pH
Being worth to 3-4, stratification, organic layer adds the wet chemical washing that 500L mass fraction is 5%, and organic layer uses quality again
Mark is that the sodium-chloride water solution washing of 10% is to neutral.Feed liquid is through anhydrous magnesium sulfate dehydration, activated carbon decolorizing, decompression precipitation
After, add 500L normal hexane and crystallize 1h in 20-25 DEG C, more by centrifugation, 40 DEG C dry after the 4-chloro-3-oxo-pentanoic acid of 250kg
(4-Nitrobenzol) methyl ester, purity 98.0%.
4-chloro-3-oxo-pentanoic acid (4-Nitrobenzol) methyl ester nuclear magnetic data is as follows:
1H-NMR (400MHz, DMSO, ppm): δ 8.23 (d, J=8Hz, 2H), 7.65 (d, J=8Hz, 2H), 5.31 (s,
2H), 4.86 (q, J=8Hz, 1H), 3.94-4.03 (m, 2H), 1.54 (d, J=8Hz, 3H)；
13C-NMR(100MHz,DMSO,ppm):δ19.33,45.17,58.59,64.93,123.47,128.45,
143.45,147.07,166.49,197.93；
The preparation of compound 2S-AM2 (in structural formula, X is Cl):
Hydrazoic acid,sodium salt 66g and sodium bicarbonate 84g is dissolved in 1680ml water and obtains solution A.Acetone 312ml is put in flask,
4-chloro-3-oxo-pentanoic acid (4-Nitrobenzol) methyl ester 286g, stir molten clearly.Temperature control 20～25 DEG C, drip solution A.Temperature control-10 again
～-5 DEG C, drip mesyl chloride 120g, drip and finish in-10～-5 DEG C of reaction 5h.After reaction terminates, add dichloromethane 624ml, stir
Mix 20min, stand 30min, layering.Organic facies successively with 3% sodium bicarbonate aqueous solution 500ml, purified water 500ml wash.
Organic facies is through anhydrous sodium sulfate dehydration, activated carbon decolorizing, decompression precipitation.Add normal hexane 156ml and stir 2h in 20-25 DEG C.Take out
Filter, in 40-50 DEG C of dry 8h, obtains 4-chloro-2-diazonium-3-oxo-pentanoic acid (4-Nitrobenzol) methyl ester 30g, purity 98.5%.
4-chloro-2-diazonium-3-oxo-pentanoic acid (4-Nitrobenzol) methyl ester nuclear magnetic data is as follows:
13C NMR(400HMz,DMSO-d6):δ186.2,159.9,147.2,143.1,28.5,123.6,75.4,65.3,
53.9,19.7。
1H NMR(400MHz,CDCl3-d): δ 8.27 (d, 2H), 7.55 (d, 2H), 5.43～5.35 (m, 1H), 5.38 (s,
2H)m,1.65(d,3H)。
The preparation of compound A-28:
28.7kg compound 4-AA (in compound A, R is t-Butyldimethylsilyl) is dissolved in 57L oxolane,
Add 8.5kg zinc powder, after temperature rising reflux 30min, be cooled to 10 DEG C.It is added dropwise to 34.3kg compound 2S-AM2 (X in structural formula again
For Cl) it is dissolved in the solution of 103L oxolane, react 3h in 0 DEG C.After reaction terminates, it is filtered to remove insoluble matter.Feed liquid is through decompression
After precipitation, addition 150L dichloromethane stirring is molten clearly, washed once at the dilute hydrochloric acid adding 50L 5%, then the chlorine with 50L 5%
Changing sodium water solution to wash to neutral, the precipitation that reduces pressure after washing is to the most dry, and addition 100L hexamethylene stirs 1h in 20～25 DEG C, then
By centrifugation, compound A-28-2 of 46.1kg, molar yield 91.3%, purity 99.0% are obtained after 40 DEG C of drying.
The structure detection data of compound A-28-2 are reported compared with document, it was demonstrated that the feasibility of the present invention.
Embodiment 2:
The preparation of compound 2S-AM2 (in structural formula, X is bromine) obtains, wherein according to method synthesis similar in embodiment 1
Raw material 4-bromo-3-oxo-pentanoic acid (4-Nitrobenzol) methyl ester can be selected for existing commercially available prod, or uses in similar embodiment 1
Method prepare.
The preparation of compound A-28:
24.5kg compound A (in formula, R is that trimethyl is silica-based) is dissolved in 80L 2-methyltetrahydrofuran, is adding
8.5kg zinc powder, after temperature rising reflux 30min, is cooled to 0 DEG C.It is added dropwise to 46.3kg compound 2S-AM2 (in structural formula, X is bromine) again
It is dissolved in the solution of 150L 2-methyltetrahydrofuran, reacts 5h in 5 DEG C.After reaction terminates, it is filtered to remove insoluble matter.Feed liquid is through subtracting
After pressure-off is molten, addition 200L chloroform stirring is molten clearly, washed once at the dilute sulfuric acid adding 70L 3%, then with 70L's 8%
Sodium-chloride water solution washing is to neutral, and the precipitation that reduces pressure after washing, to the most dry, add 120L normal hexane and stirs 1h in 20～25 DEG C,
The most by centrifugation, 50 DEG C dry after compound A-28-1 of 45.3kg, molar yield 98%, purity 99.1%.
The structure detection data of compound A-28-1 are reported compared with document, it was demonstrated that the feasibility of the present invention.
Claims (10)
1. the preparation method of an antibiotic medicine intermediate, it is characterised in that including: compound A and compound 2S-AM2 exists
In the presence of metallic catalyst, reacting in organic solvent A, reaction terminates, and post processing obtains compound A-28；
The structure of described compound A is as follows:
In above formula, R is hydrogen or trimethyl is silica-based or t-Butyldimethylsilyl；
The structure of described compound 2S-AM2 is as follows:
In above formula, X represents F or Cl or Br or I；
The structure of described compound A-28 is as follows:
The preparation method of antibiotic medicine intermediate the most according to claim 1, it is characterised in that concrete steps include:
(I) compound A is dissolved in organic solvent A, adds metal, after temperature reaction completely, cooling；
(II) it is added dropwise to compound 2S-AM2 and is dissolved in the solution of organic solvent A, after reaction terminates, be filtered to remove insoluble matter；
(III), after feed liquid desolvation, organic solvent B stirring is added molten clearly；
(IV) washing is to neutral；
(V) removing organic phase solvent, adds organic solvent C stirred crystallization, separates product, obtains compound A-28 after drying.
The preparation method of antibiotic medicine intermediate the most according to claim 1 and 2, it is characterised in that described metal with
The mol ratio of compound A is (1.0～3.0): 1；The described metal one or both mixture in zinc, magnesium.
The preparation method of antibiotic medicine intermediate the most according to claim 1 and 2, it is characterised in that described compound
The mol ratio of 2S-AM2 and compound A is (1.0～2.0): 1.
The preparation method of antibiotic medicine intermediate the most according to claim 1 and 2, it is characterised in that described organic molten
Agent A be oxolane, 2 upper for the oxolane of C1～C4 alkyl, 3 upper for the oxolane of C1～C4 alkyl, 1,4-bis-
A kind of or the most multiple mixture in oxygen six ring.
The preparation method of antibiotic medicine intermediate the most according to claim 2, it is characterised in that in step (I), reaction
Temperature is-10 DEG C of stable reflux temperatures to organic solvent A, and after this step reaction is complete, the temperature of cooling is-20～40 DEG C.
The preparation method of antibiotic medicine intermediate the most according to claim 2, it is characterised in that in step (II), instead
Answering temperature is 0～30 DEG C.
The preparation method of antibiotic medicine intermediate the most according to claim 2, it is characterised in that organic solvent B is two
A kind of or the most multiple mixture in chloromethanes, chloroform, carbon tetrachloride, dichloroethanes, ethyl acetate, toluene, benzene.
The preparation method of antibiotic medicine intermediate the most according to claim 2, it is characterised in that organic solvent C is C5
～a kind of or the most multiple mixture in the alkane of C10, ether.
The preparation method of antibiotic medicine intermediate the most according to claim 9, it is characterised in that organic solvent C is ring
One or both mixture in hexane, normal hexane.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113880726A (en) * | 2021-10-14 | 2022-01-04 | 南昌大学 | A kind of method for efficiently synthesizing diazo compounds |
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| CN102491992A (en) * | 2011-11-24 | 2012-06-13 | 山东润泽制药有限公司 | Method for preparing carbapenem type antibiotic key intermediate 4-BMA |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102491992A (en) * | 2011-11-24 | 2012-06-13 | 山东润泽制药有限公司 | Method for preparing carbapenem type antibiotic key intermediate 4-BMA |
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| MICHAEL B. SMITH等: "《March高等有机化学--反应、机理与结构》", 30 June 2009, 化学工业出版社 * |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113880726A (en) * | 2021-10-14 | 2022-01-04 | 南昌大学 | A kind of method for efficiently synthesizing diazo compounds |
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Application publication date: 20161123 |