CN102993102B - The synthetic method of [1-methyl-2-(hydroxamic acid base in 7 '-heptan)-5-N, N-bis-(2 '-chloroethyl)]-1H-benzimidazole - Google Patents
The synthetic method of [1-methyl-2-(hydroxamic acid base in 7 '-heptan)-5-N, N-bis-(2 '-chloroethyl)]-1H-benzimidazole Download PDFInfo
- Publication number
- CN102993102B CN102993102B CN201110275348.8A CN201110275348A CN102993102B CN 102993102 B CN102993102 B CN 102993102B CN 201110275348 A CN201110275348 A CN 201110275348A CN 102993102 B CN102993102 B CN 102993102B
- Authority
- CN
- China
- Prior art keywords
- reaction
- methyl
- benzimidazole
- bis
- chloroethyl
- 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.)
- Active
Links
- 0 *C(CCCCCCC(O*)=O)=N Chemical compound *C(CCCCCCC(O*)=O)=N 0.000 description 1
Abstract
The invention discloses one [1 methyl 2 (7' hydroxamic acid in heptan base) 5 N, N bis-(2' chloroethyl)] synthetic method of 1H benzimidazole, it is that the raw material substitution lower boiling ethylene oxide synthesis of severe toxicity prepares NL 101 i.e. [1 methyl 2 (7' hydroxamic acid in heptan base) 5 N with monoxone, N bis-(2' chloroethyl)] 1H benzimidazole, and integrate multistep reaction one pot and carry out, eliminate separating-purifying step, synthetic route is short, reaction environment especially temperature, pressure etc. is safely controllable, environmental protection；A series of midbody compounds obtained by the invention also discloses in synthesis NL 101 reaction, NL 101 obtained by synthetic route of the present invention, its high purity 95% is found through analysis and characterization, find that its purity is more than 99% through recrystallizing and refining again, efficiency of pcr product is high, easily operation, beneficially industrial-scale production.
Description
Technical field
The present invention relates to the synthetic method of the antitumor drug of a kind of Antibiotic FR 901228, be specifically related to one
Plant the synthetic method of [1-methyl-2-(hydroxamic acid base in 7 '-heptan)-5-N, N-bis-(2'-chloroethyl)]-1H-benzimidazole.
Background technology
At present, the design of Antibiotic FR 901228 presents Mutiple Targets trend, a most single medicine
Molecule has activity and other a certain enzyme or the inhibitory activity of target spot of inhibition of histone deacetylase concurrently.This single molecule
The Mutiple Targets medicine administering drug combinations etc. that compares there is many advantages, there is difference including can effectively overcome each drug component
Problem (Meunier, the B.Acc.Chem.Res.2008,41,69. such as dissolubility, different pharmacokinetic parameters；Tsogoeva,
S.B.Mini-Rev.Med.Chem.2010,10,773.)。
Vorinostat (SAHA) is first inhibition of histone deacetylase in the world of Merck & Co., Inc.'s exploitation
(histone deacetylase；HDAC) new type anticancer medicine, this medicine obtained in U.S. FDA approval on October 6th, 2006
City, is used for treating T lymphocytoma, and this medicine is ratified by FDA as rare sick medicine.The change of Vorinostat (see formula III)
Formula is C14H20N2O3, CA accession number is 149647-78-9, and chemical constitution is:
The main structure of histon deacetylase (HDAC) crystal includes: the active site of enzyme is pocket shape, and activity
Center zinc ion is aboutDeep " pocket " bottom, the narrowest place of " pocket " is only(Finnin,M.S.；Donigian,
J.R.；Cohen,A.；et al.Nature 1999,401,188.).According to said structure feature, anticarcinogen existing to market
(general entitled bendamustine, chemical formula is C to thing bendamustine15H19Cl2N3O2) carry out structural modification, extend its end
Carboxyl chain and be transformed into hydroxamic acid structure so that it is both retained the pharmacophore of bendamustine, there is DNA alkylating,
Activity (Chen, the Y. of lucky energy inhibition of histone deacetylase again；Chen,Y.W.O.Patent 2010/085377,
2010.).Experimental result shows, structural modification gained compound is [1-methyl-2-(hydroxamic acid base in 7 '-heptan)-5-N, N-bis-
(2'-chloroethyl)]-1H-benzimidazole (i.e. NL-101 is the most all called for short NL-101, sees formula I) with listed histone deacetylase
Changing enzyme inhibitor vorinostat (see formula III) and have the histon deacetylase (HDAC) inhibitory activity compared favourably, it is to cancerous cell
Extracorporeal extracorporeal suppression will good dozens to one hundred times than bendamustine (see formula II).
As follows to the structural modification of bendamustine (II):
Publication No. WO 2010085377, the patent public affairs of invention entitled " Hydroxamic Acid Derivatives "
Having opened the synthetic method of a kind of NL-101, synthesis step is as follows: 1. by DNFB methylamine, 2. obtains after amination
N-methyl-2 arrived, 4-dinitro palladium carbon is reduced to 2-amino-4-nitro-N-methylaniline, 3. reduzate and suberic acid
Anhydride reactant obtains 8-(2-methylamino-5-nitrobenzophenone) amino-8-oxo octanoic acid, the most again with palladium carbon hydrogenating reduction nitro cyclization
Obtain (1-methyl-2-enanthic acid-5-amino)-1H-benzimidazole, the 5. ammonia of (1-methyl-2-enanthic acid-5-amino)-1H-benzimidazole
Base section again with reacting ethylene oxide, and through thionyl chloride chloro, obtain containing chlormethine structure [1-methyl-2-(7'-enanthic acid)-
5-N, N-bis-(2'-chloroethyl)]-1H-benzimidazole, 6. [1-methyl-2-(7'-enanthic acid)-5-N, N-bis-(2'-chloroethyl)]-
The carboxy moiety of 1H-benzimidazole reacts with ethyl chloroformate, then obtains the NL-101 such as formula I the most again with azanol reaction.
This patent is disadvantageous in that: the reaction scheme 1. synthesizing NL-101 is longer, and production cost is higher；2. step is synthesized
The oxirane used in rapid, boiling point is relatively low is 10.73 DEG C, is colourless inflammable gas under normal temperature and pressure state；Therefore react
Time typically require that oxirane is cooled to liquid rear is transferable, if temperature exceedes boiling point accidentally in transfer process, can become
Gas, volume acutely expands, and causes explosion danger；3. the gas of oxirane is poisonous, if loss is to meeting in production environment accidentally
Jeopardize the healthy of workman；4. 2., 3. as described in, this synthetic route is unfavorable for temperature control, and production environment is dangerous, therefore inapplicable
In industrialized production.
Summary of the invention
The invention provides a kind of synthesis [1-methyl-2-(hydroxamic acid base in 7 '-heptan)-5-N, N-bis-(2'-chloroethyl)]-
The new method of 1H-benzimidazole, selecting monoxone is raw material substitution oxirane, safety, and nonhazardous easily operates, and solves existing
There is synthesis NL-101 reaction scheme in technology longer, be unfavorable for temperature control, the unsafe technological deficiency of production environment.
For achieving the above object, present invention employs following technical scheme:
For ease of reference, the following abbreviation used in the present invention or definition, they have an implication given below:
Me=methyl
Et=ethyl
Ac=acyl group
TEA=triethylamine
Pd/C=palladium carbon
Et2O=ether
MeOH=methanol
Oxirane=oxirane
DMF=dimethylformamide
THF=oxolane
EDCI=1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride
DMAP=4-lutidines
DCC=N, N'-dicyclohexyl carbodiimide
HBTU=BTA-N, N, N', N'-tetramethylurea hexafluorophosphate
HOBt=hydroxy benzo triazole
RT=room temperature, is often referred to 20～25 DEG C
1 normal atmosphere=1.013 × 105Pascal
" alkaline environment " in the present invention refer to certain compounds in water or solvent in alkalescence, ie in solution pH > 7.0, should
Compounds includes hydride, hydroxide, alkali metal salt or alkoxide, or the compound of such as amine etc, and they can be at water
Or adsorber acid radical ion or accept proton in solvent.The example of above-mentioned alkali compounds includes but are not limited to, such as hydride bag
Include but be not limited to the hydride of potassium, sodium, lithium；As hydroxide includes but not limited to NaOH, LiOH, Mg (OH)2、Ca(OH)2Deng；
Alkali metal salt or alkoxide include but not limited to sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, lithium diisopropylamine, tertiary fourth
Potassium alcoholate, sodium tert-butoxide etc.；Alkylating two silicon nitrides such as hexamethyl two silicon potassium nitride, hexamethyl two silicon lithium nitride etc.；Alkyl
Amine such as triethylamines etc., the most above-mentioned alkoxide, alkyl are preferably the C of straight or branched1-6Alkyl.
" sour environment " in the present invention refer to certain compounds in water or solvent in acidity, ie in solution pH < 7.0, should
Compounds can dissociate generation hydrogen cation or acid ion in water or solvent, includes but not limited to following acid: hydrochloric acid (or
Concentrated hydrochloric acid), sulphuric acid (or concentrated sulphuric acid), hydrobromic acid, phosphoric acid, acetic acid, trifluoroacetic acid, sulphonic acids such as benzenesulfonic acid or p-methyl benzenesulfonic acid,
Tartaric acids such as L-TARTARIC ACID, lactic acid class, aspartic acid class, BCl3、BBr3Etc..
One [1-methyl-2-(hydroxamic acid base in 7 '-heptan)-5-N, N-bis-(2'-chloroethyl)]-1H-that the present invention provides
The synthetic method of benzimidazole, overall reaction route is as follows:
R in above-mentioned overall reaction route is hydrogen, methyl, formoxyl or methanesulfonic acid base, R1For C1-6Alkyl, phenyl, benzyl
Or phenethyl, X is Cl, Br, I or OH.
Above-mentioned overall reaction route, mainly includes following four step synthesis steps:
(1) such as the raw material 2 of formula IV, 4-dinitroanilines, addition is mixed with suberic acid monoester or its acylate
To organic solvent, amidation process under alkaline environment, obtain 8-(2, the 4-dinitrophenyl) methylamino-8-oxygen such as formula V
For caprylate, reaction equation is as follows:
The organic solvent of reaction is selected from dimethylformamide, ethyl acetate, THF, dichloromethane, acetonitrile, toluene, dimethylbenzene
In one or more；Reaction temperature is 60～150 DEG C, is the reflux temperature of respective reaction solvent, such as the boiling of ethyl acetate
Point is 152.8 DEG C, and the boiling point of dimethylbenzene is 137～140 DEG C, and the boiling point of acetonitrile is 81.1 DEG C, and the boiling point of THF is 65.4 DEG C.
(2) step (1) products therefrom V, carries out catalytic hydrogenating reduction in organic solvent, and reaction temperature is 0～60 DEG C,
Reaction pressure is 1～7 normal atmosphere, and hydrogenating reduction cyclization obtain intermediate such as formula VII；Directly filter catalyst, add
Organic solvent, sour environment or alkaline environment or directly heat lower continue reaction, reaction temperature be coordinative solvent system return
Stream temperature (numerical value of solvent reflux temperature is as previously mentioned), intermediate VII dehydration obtains [1-methyl-2-(the 7 '-enanthic acid such as formula VIII
Ester group)-5-amino]-1H-benzimidazole or its salt, reaction equation is as follows:
One or more in ruthenium, nickel, platinum, palladium of the catalyst of reaction, above-mentioned catalyst generally exists with metal load
Form on activated carbon occurs, if catalyst is that the then many of palladium occur with palladium carbon form；Organic solvent is selected from methanol, ethanol, THF
In one or more；
(3) step (2) products therefrom VIII, in organic solvent with chloroacetate reaction, obtains [1-methyl-the 2-such as formula Ⅸ
(7 '-enanthic acid ester group)-5-N, N-bis-(2'-chloracetyl)]-1H-benzimidazole；Add reducing agent and continue reaction, at room temperature
The carbonyl of compound Ⅸ is reduced, and obtains the compound containing chlormethine structure, i.e. as formula Ⅹ reduzate [1-methyl-2-(7 '-
Enanthic acid ester group)-5-N, N-bis-(2'-chloroethyl)]-1H-benzimidazole, reaction temperature is 20～90 DEG C, and reaction equation is as follows:
The organic solvent of reaction is selected from THF, dichloromethane, and dimethylformamide, in acetonitrile, diisopropyl ether, dioxane
One or more；One or more in borine, borine-oxolane, lithium borohydride, sodium borohydride of reducing agent；
(4) step (3) gained reduzate Ⅹ, the most anti-with azanol or O-(Pentamethylene oxide .-2-base) azanol
Should, obtain target compound [1-methyl-2-(hydroxamic acid base in 7 '-heptan)-5-N, N-bis-(2'-chloroethyl)]-1H-such as formula I
Benzimidazole, reaction equation is as follows:
The organic solvent of reaction is selected from methanol or ethanol.
In preferred technical scheme, the initiation material 2 of the present invention, 4-dinitroanilines (i.e. formulaFor N-methyl-2,4-dinitroaniline or 2,4-dinitroaniline, (i.e. in formula IV, R is-CH3Or
H).Wherein, R be H i.e. initiation material be 2, during 4-dinitroaniline, the step (1) of the present invention except above-mentioned single step reaction prepare such as
Outside product 8-(2, the 4-dinitrophenyl) methylamino-8-oxo octanoic acid ester of formula V, it is also possible to by following two-step reaction route
Prepare:
I.e. 2,4-dinitroaniline is mixed and added into organic solvent with suberic acid monoester or its acylate, at alkalescence ring
Amidation process under border, reaction temperature is 60～150 DEG C, obtain intermediate 8-(2, the 4-dinitrophenyl) amino such as formula VI-
8-oxo octanoic acid ester；Adding methylating reagent and continue reaction, hydrogen on intermediate VI nitrogen is methylated obtains product formula V；Reaction
Methylating reagent selected from dimethyl sulfate, iodomethane or dimethyl sulfoxide；The organic solvent of reaction and above-mentioned overall reaction route
Organic solvent included in step (1) is identical.
Certainly, the initiation material 2 in the present invention, 4-dinitroanilines, in formula IV, R removes as above-mentioned first
Outside base or hydrogen, it is also possible to straight for other versions containing methyl group, even ethyl, propyl group etc. such as formoxyl, methanesulfonic acid base
Chain or the version of branched alkyl, if meet through add methylating reagent or after other reacts the nitrogen of products therefrom formula V
On be connected to the invention thinking of a methyl,.
Work as formulaMiddle X is that (i.e. this compound is suberic acid list to the halogens such as Cl, Br, I
Ester acylate) time, reaction is carried out by foregoing synthetic route；In preferred technical scheme, if formulaWhen middle X is OH (i.e. this compound is suberic acid monoester), overall reaction route steps (1) of the present invention
In, it is also possible to add coupling reaction reagent D MAP or EDCI, prepare such as intermediate 8-(2, the 4-dinitros of formula VI after coupling reaction
Base phenyl) amino-8-oxo octanoic acid ester.
In the overall reaction route steps (1) of the present invention, either two-step reaction or single step reaction prepare product V, excellent
In the technical scheme of choosing, reaction temperature is preferably 100～150 DEG C, and the organic solvent of reaction is preferably acetonitrile or dimethylbenzene, methyl
Changing reagent and be preferably dimethyl sulfate, the alkali added in reaction is preferably potassium carbonate.
In the present invention step (2) product V except above-mentioned in addition to catalytic hydrogenating reduction cyclization obtain intermediate VII, it is also possible to
Intermediate VII is prepared by methods such as sodium hydrosulfite-acetic acid reduction, acetic acid-iron powder reducing, acetic acid-zinc powder reductions；Optimization technique side
In case, intermediate VII can (as added hydrochloric acid etc.), dehydration obtains [1-methyl-2-(the 7 '-enanthic acid such as formula VIII under sour environment
Ester group)-5-amino] respective salt of-1H-benzimidazole, it is also possible to (as added sodium hydride, hydroxide under alkaline environment
Potassium etc.) or directly heat lower dehydration and obtain [1-methyl-2-(7 '-enanthic acid ester group)-5-the amino]-1H-benzimidazole such as formula VIII.
In the overall reaction route steps (2) of the present invention, reaction pressure is preferably 2.5～7 normal atmospheres, and catalyst is excellent
Select carrier palladium (as it was previously stated, what catalyst generally occurred, also known as carrier palladium), i.e. palladium with metal load form on activated carbon
Content is the palladium carbon of 5～10%, and organic solvent is preferably methanol, and the acid added in reaction is preferably concentrated hydrochloric acid.
In the overall reaction route steps (3) of the present invention, reaction temperature is preferably 40～90 DEG C, and organic solvent is preferably THF,
Reducing agent is preferably borine-oxolane.
In the overall reaction route steps (4) of the present invention, if adding azanol, then reduzate Ⅹ can prepare through single step reaction
Target compound I；Except, it is also possible to adding O-(Pentamethylene oxide .-2-base) azanol, now reduzate Ⅹ is through following multistep reaction
Route equally prepare as formula I target compound NL-101's or its salt form:
I.e. reduzate Ⅹ obtains intermediate Ⅺ through hydrolysis, and intermediate Ⅺ and O-(Pentamethylene oxide .-2-base) azanol exist
In organic solvent, reaction obtains intermediate Ⅻ, and intermediate Ⅻ reacts under sour environment and obtains target chemical combination in described step (4)
Thing I or its salt form；The organic solvent of reaction is selected from THF, dichloromethane, dimethylformamide, acetonitrile, methanol, dioxane
In one or more.
In the multistep reaction of above-mentioned steps (4) when reduzate Ⅹ obtains intermediate Ⅺ through hydrolysis, hydrolysis
Including acid hydrolysis or alkaline hydrolysis, wherein during acid adding, hydrolysing agent is preferably concentrated hydrochloric acid, and hydrolysis temperature is preferably 80～100
℃；When adding alkali, hydrolysing agent is preferably Lithium hydrate, and reaction dissolvent is preferably water or methanol and water mixed solvent, and hydrolysis temperature leads to
Often less than room temperature, preferably 0～15 DEG C.
The multistep reaction of above-mentioned steps (4) obtains through additive reaction with O-(Pentamethylene oxide .-2-base) azanol when intermediate Ⅺ
During intermediate Ⅻ, one or more in THF, dichloromethane, DMF, acetonitrile of reaction dissolvent, preferably THF；Instead
Additive is answered to include DCC, DMAP, HBTU, triethylamine, HOBt, N-methylmorpholine or carbonylic imidazole, preferably DCC.
In the multistep reaction of above-mentioned steps (4) under intermediate Ⅻ is at sour environment reaction obtain target compound I or its
During salt, the acid that sour environment adds preferably concentrated hydrochloric acid；Reaction dissolvent one in methanol, dioxane, the dichloromethane or
Several, preferably methanol.
As described in the background art, if the target compound NL-101 of formula I is the structural modification to bendamustine, retain
Bendamustine pharmacophore part-structure, and extend the bendamustine carboxylic acid long-chain moiety structure containing 5 carbon, it is transformed into
Hydroxamic acid structure containing 8 carbon is NL-101, therefore considers the convenient of actual synthetic reaction, therefore selects suberic acid monoester
Single acyl chlorides reacts with initiation material；Except, from synthesis thinking for, by the suberic acid in overall reaction route of the present invention
Monoesters or its acylate replace to such as formula(X、R1Defined as described above, n be 5～10 arbitrary from
So number) shown in version, all can prepare such as the target compound NL-of formula I by above-mentioned synthetic reaction route based on the present invention
The derivant of 101 different chain length.
Present invention also offers a class for preparing aforesaid target compound I (i.e. [1-methyl-2-(7 '-heptan different hydroxyl oxime
Acidic group)-5-N, N-bis-(2'-chloroethyl)]-1H-benzimidazole, be called for short NL-101) intermediate V～intermediate Ⅻ, above-mentioned in
Mesosome is following compound:
Wherein R1For C1-6Alkyl, phenyl or C1-6Alkyl is at benzene
Monosubstituted or polysubstituted group is carried out on ring optional position." polysubstituted " of indication herein, including disubstituted, three replacements etc. originally
Skilled person is known in the nuclear substituted several frequently seen mode of benzene, substituent group C1-6Alkyl the position of substitution on phenyl ring,
Including o-, m-, to three kinds of forms；" the C of indication herein1-6Alkyl ", refer to the straight or branched alkyl of 1-6 carbon atom,
Preferably methyl and ethyl.
Preferably in technical scheme, the above-mentioned intermediate for preparing aforesaid target compound NL-101, walk in the present invention
Suddenly in the reaction of (1)～step (4), in involved intermediate V～the formula of intermediate X, R1It is methyl；I.e. intermediate
V～intermediate X, be followed successively by six compounds of following structure:
Present invention have the advantage that
The invention discloses one [1-methyl-2-(hydroxamic acid base in 7 '-heptan)-5-N, N-bis-(2'-chloroethyl)]-1H-
The synthetic method of benzimidazole, is that the raw material substitution lower boiling ethylene oxide synthesis of severe toxicity prepares NL-101 i.e. [1-with monoxone
Methyl-2-(hydroxamic acid base in 7 '-heptan)-5-N, N-bis-(2'-chloroethyl)]-1H-benzimidazole, and integrate multistep reaction one pot
Carrying out, eliminate separating-purifying step, synthetic route is short, and reaction environment especially temperature, pressure etc. is safely controllable, green ring
Protect；A series of midbody compounds obtained by the invention also discloses in synthesis NL-101 reaction, synthetic route institute of the present invention
The NL-101 prepared, finds its high purity 95% through analysis and characterization, then finds that its purity, more than 99%, is produced through recrystallizing and refining
Thing yield is high, easily operates, beneficially industrial-scale production.
Detailed description of the invention
Below in conjunction with specific embodiment, the present invention is further described, but protection scope of the present invention is without being bound by as follows
Embodiment scope of disclosure.
Embodiment 1:
Step (1)
First, addition 2 in 250mL reaction bulb, 4-dinitroaniline (10.0g, 54.6mmol) and toluene (100mL),
Nitrogen is protected, and is stirred at room temperature, then drips suberic acid mono-methyl list acyl chlorides (13.5g, 65.5mmol).Drip and finish, be warming up to backflow,
TLC tracks to reaction end, after about 24h, is cooled to 60 DEG C.Adding water (100mL), vacuum rotary steam removes toluene, separates out yellow
Solid, oven drying at low temperature, obtain 8-(2,4-dinitrophenyl) amino-8-oxo octanoic acid methyl ester: 18.6g, 96.4%.
The 8-(2,4-dinitrophenyl) amino-8-oxo octanoic acid methyl ester (18.6g, 52.6mmol) of above-mentioned gained is added
Room temperature reaction in acetonitrile (50mL), dropping dimethyl sulfate (8.0g, 63.1mmol) and potassium carbonate (14.5g,
105.2mmol), TLC follows the tracks of reaction to terminal, about 24h.Sucking filtration removes filter cake, acetonitrile drip washing, carefully drips water toward mother solution
(250mL), room temperature, it is stirred vigorously, separates out yellow solid, sucking filtration, oven drying at low temperature, obtain product 8-(2,4-dinitrophenyl) first ammonia
Base-8-oxo octanoic acid methyl ester: 17.8g, 92.1%.
Step (2)
By 8-(2,4-dinitrophenyl) methylamino-8-oxo octanoic acid methyl ester (17.8g, 48.5mmol), 5% palladium carbon
(1.8g) being placed in methanol (150mL), under 2.5 atmospheric pressure, logical hydrogen reacts about 18h.Sucking filtration, mother solution adds concentrated hydrochloric acid
(4.5mL), heating reflux reaction 3.5h.It is evaporated to 1/4 volume, adds the oxolane (150mL) of heat, be stirred vigorously,
Separate out brown solid, sucking filtration, [1-methyl-2-(7 '-methyl heptanoate base)-5-amino]-1H-benzimidazole hydrochlorate:
13.8g, 87.3%.
Step (3)
By [1-methyl-2-(7 '-methyl heptanoate base)-5-amino]-1H-benzimidazole hydrochlorate (13.8g,
42.4mmol), monoxone (83.7g, 890mmol) joins in oxolane (20mL), is stirred to dissolve.Water-bath temperature control, slow
Slowly drip borine-oxolane (300mL, about 300mmol), drip and finish, continue room temperature reaction 5h, add methanol cancellation reaction.Instead
Liquid is answered to be concentrated into 1/3 volume, under ice cooling, 4, with in sodium carbonate liquor and pH to 7～8.Sucking filtration, with water, methyl tert-butyl ether
Drip washing, reduce pressure drying at room temperature, obtain sepia solid [1-methyl-2-(7 '-methyl heptanoate base)-5-N, N-bis-(2'-chloroethyl)]-
1H-benzimidazole: 16.9g, 96.2%.
Step (4)
Oxammonium hydrochloride. (56.7g, 816mmol) is mixed in methanol (145mL), pour into potassium hydroxide (45.8g,
Methanol (270mL) solution 816mmol), 40 DEG C of stirring 15min, sucking filtration, obtain the methanol solution of azanol, add [1-methyl-2-
(7 '-methyl heptanoate base)-5-N, N-bis-(2'-chloroethyl)]-1H-benzimidazole (16.9g, 40.8mmol), stir 3h, will be anti-
Answering liquid to be poured in frozen water (1300mL), the acetum of dropping 3N is 6～7 to pH, separates out a large amount of white powder solid, sucking filtration,
Washing, dries, obtains white solid [1-methyl-2-(hydroxamic acid base in 7 '-heptan)-5-N, N-bis-(2'-chloroethyl)]-1H-benzo
Imidazoles (is called for short NL-101), i.e. target compound I: 15.0g, and 88.5%；Fusing point: 165-168 DEG C；IR νmax(KBr)/cm-1:
3266,2930,2858,1646,1497,1441,1156,733；1H NMR(DMSO-d6,500MHz)δ:10.41(s,1H,NH),
7.32 (d, J=9.0Hz, 1H, Ar), 6.92 (d, J=2.0Hz, 1H, Ar), 6.78 (dd, J1=2.0Hz, J2=9,0Hz, 1H,
Ar),3.71(s,8H,2×CH 2CH2Cl),3.66(s,3H,NCH3), 2.79 (t, J=7.5Hz, 2H, C (O) CH2),1.96(t,
J=7.3Hz, 2H, CCH2),1.74-1.71(m,2H,CH2),1.52-1.49(m,2H,CH2),1.38-1.29(m,4H,CH 2CH2)；13C NMR(DMSO-d6,125MHz)δ:169.1,155.1,143.3,142.2,129.3,110.0,109.9,
102.4,53.5,41.4,32.2,29.4,28.4,28.3,26.7,26.4,25.0；EI-MS m/z (%): 414 (2, M+),
398(27),347(100),321(26),298(60),285(52),186(38),172(37),158(31)。
Embodiment 2:
Step (1)
N-methyl-2,4-dinitroaniline (10.8g, 54.6mmol) and dimethylbenzene is added in 250mL reaction bulb
(100mL), nitrogen is protected, return stirring, then drips suberic acid mono-methyl list acyl chlorides (13.5g, 65.5mmol).Drip and finish, heat up
To backflow, TLC tracks to reaction end, after about 24h, is cooled to 60 DEG C.Adding water (100mL), vacuum rotary steam removes dimethylbenzene,
Separate out yellow solid, oven drying at low temperature, obtain product 8-(2,4-dinitrophenyl) methylamino-8-oxo octanoic acid methyl ester: 18.3g,
91.2%.
Step (2)
By 8-(2,4-dinitrophenyl) methylamino-8-oxo octanoic acid methyl ester (18.3g, 50.0mmol), 10% palladium carbon
(1.0g) being placed in methanol (150mL), under 3 atmospheric pressure, logical hydrogen reacts about 8h.Sucking filtration, mother solution adds concentrated hydrochloric acid
(4.5mL), heating reflux reaction 4h.It is evaporated to 1/4 volume, adds the oxolane (150mL) of heat, be stirred vigorously, analysis
Go out brown solid, sucking filtration, [1-methyl-2-(7 '-methyl heptanoate base)-5-amino]-1H-benzimidazole hydrochlorate:
14.8g, 91.6%.
Step (3)
By [1-methyl-2-(7 '-methyl heptanoate base)-5-amino]-1H-benzimidazole hydrochlorate (14.8g,
45.5mmol), monoxone (89.8g, 955mmol) joins in diisopropyl ether (20mL), is stirred to dissolve.Water-bath temperature control, slowly
Dropping sodium borohydride (11.3g, 300mmol), drips and finishes, and continues room temperature reaction 5h, adds methanol cancellation reaction.Reactant liquor is concentrated into
1/3 volume, under ice cooling, 4, with in sodium carbonate liquor and pH to 7～8.Sucking filtration, with water, methyl tert-butyl ether drip washing, pressure-reducing chamber
Temperature is dried, and obtains sepia solid [1-methyl-2-(7 '-methyl heptanoate base)-5-N, N-bis-(2'-chloroethyl)]-1H-benzo miaow
Azoles: 17.8g, 94.7%.
Step (4)
Oxammonium hydrochloride. (59.7g, 859mmol) is mixed in methanol (150mL), pour into potassium hydroxide (48.2g,
Methanol (280mL) solution 859mmol), 40 DEG C of stirring 15min, sucking filtration, obtain the methanol solution of azanol, add [1-methyl-2-
(7 '-methyl heptanoate base)-5-N, N-bis-(2'-chloroethyl)]-1H-benzimidazole (17.8g, 43.0mmol), stir 4h, will be anti-
Answering liquid to be poured in frozen water (1300mL), the acetum of dropping 3N is 6～7 to pH, separates out a large amount of white powder solid, sucking filtration,
Washing, dries, obtains white solid [1-methyl-2-(hydroxamic acid base in 7 '-heptan)-5-N, N-bis-(2'-chloroethyl)]-1H-benzo
Imidazoles (is called for short NL-101), i.e. target compound I: 16.5g, and 92.3%.
Embodiment 3:
Step (1)
First, addition 2,4-dinitroaniline (10.0g, 54.6mmol), suberic acid mono-methyl in 250mL reaction bulb
(12.3g, 65.5mmol) and dimethylformamide (60mL), nitrogen protect, be stirred at room temperature, add DMAP (8.0g,
65.5mmol).Being warming up to backflow, TLC tracks to reaction end, after about 36h, is joined by reactant liquor in frozen water (800mL), analysis
Go out yellow and stick shape thing, stand, sucking filtration, obtain glutinous shape thing, use ether drip washing, solidification, oven drying at low temperature, obtain 8-(2,4-dinitrophenyl)
Amino-8-oxo octanoic acid methyl ester: 15.1g, 78.3%.
The 8-(2,4-dinitrophenyl) amino-8-oxo octanoic acid methyl ester (15.1g, 42.7mmol) of above-mentioned gained is added
Room temperature reaction in dimethylformamide (50mL), dropping iodomethane (7.3g, 51.2mmol) and potassium carbonate (11.8g,
85.4mmol), TLC follows the tracks of reaction to terminal, about 6h.Sucking filtration removes filter cake, DMF drip washing, and mother solution is poured into frozen water (600mL)
In, stirring, separate out yellow solid, sucking filtration, oven drying at low temperature, obtain product 8-(2,4-dinitrophenyl) methylamino-8-oxo octanoic acid
Methyl ester: 14.7g, 93.7%.
Step (2)
By 8-(2,4-dinitrophenyl) methylamino-8-oxo octanoic acid methyl ester (14.7g, 40.0mmol), 5% palladium carbon
(1.5g) being placed in methanol (125mL), under 2.5 atmospheric pressure, logical hydrogen reacts about 18h.Sucking filtration, mother solution adds sodium hydroxide
(4.0mL), heating reflux reaction 3.5h.It is evaporated to 1/4 volume, adds the oxolane (125mL) of heat, be stirred vigorously,
Separate out brown solid, sucking filtration, obtain [1-methyl-2-(7 '-methyl heptanoate base)-5-amino]-1H-benzimidazole: 10.9g,
83.6%.
Step (3)
By [1-methyl-2-(7 '-methyl heptanoate base)-5-amino]-1H-benzimidazole (10.9g, 33.5mmol), chloroethene
Acid (66.1g, 700mmol) joins in oxolane (16mL), is stirred to dissolve.Water-bath temperature control, is slowly added dropwise borine-tetrahydrochysene
Furan (240mL, about 240mmol), drips and finishes, and continues room temperature reaction 5h, adds methanol cancellation reaction.Reactant liquor is concentrated into 1/3 body
Long-pending, under ice cooling, 4, with in sodium carbonate liquor and pH to 7～8.Sucking filtration, with water, methyl tert-butyl ether drip washing, decompression room temperature is done
Dry, obtain sepia solid [1-methyl-2-(7 '-methyl heptanoate base)-5-N, N-bis-(2'-chloroethyl)]-1H-benzimidazole:
12.9g, 93.1%.
Step (4)
By [1-methyl-2-(7 '-methyl heptanoate base)-5-N, N-bis-(2'-chloroethyl)]-1H-benzimidazole (12.9g,
31.1mmol) in water (60mL) solution of Lithium hydrate (1.1g, 46.7mmol), 10 DEG C of hydrolysis 4h, obtain [1-methyl-2-
(7 '-enanthic acid base)-5-N, N-bis-(2'-chloroethyl)]-1H-benzimidazole: 12.2g, 98.0%.
By [1-methyl-2-(7 '-enanthic acid base)-5-N, N-bis-(2'-chloroethyl)]-1H-benzimidazole (12.2g,
30.5mmol) it is placed in oxolane (60mL), adds N, N'-dicyclohexyl carbodiimide (7.6g, 36.6mmol), stir
Mixing, add O-(Pentamethylene oxide .-2-base) azanol (4.3g, 36.6mmol), room temperature reaction 18h, obtain intermediate Ⅻ, it is at concentrated hydrochloric acid
(8mL) in methanol (60mL) solution, 0 DEG C of hydrolysis 18h, obtain [1-methyl-2-(hydroxamic acid base in 7 '-heptan)-5-N, N-bis-
(2'-chloroethyl)] hydrochlorate of-1H-benzimidazole, i.e. the hydrochlorate of target compound I: 13.0g, 94.4%；This hydrochlorate
The aqueous solution of sodium hydroxide can neutralize and quantitatively obtain NL-101 (I).
Claims (9)
1. [1-methyl-2-(7'-hydroxamic acid in heptan base)-5-N, N-bis-(2'-chloroethyl)]-1H-benzo shown in formula I
The synthetic method of imidazoles, comprises the steps:
(1) such as the raw material 2 of formula IV, 4-dinitroanilines, mix addition with suberic acid monoester or its acylate to having
In machine solvent, reacting under alkaline environment, reaction temperature is 60～150 DEG C, obtains 8-(2, the 4-dinitrophenyl) first such as Formula V
Amino-8-oxo octanoic acid ester, reaction equation is as follows:
Described organic solvent is selected from dimethylformamide, ethyl acetate, oxolane, dichloromethane, acetonitrile, toluene, dimethylbenzene
In one or more；
(2) step (1) products therefrom V, carries out catalytic hydrogenating reduction in organic solvent, and reaction temperature is 0～60 DEG C, reaction pressure
Power is 1～7 normal atmosphere, obtains the intermediate such as Formula VII；Directly filter catalyst, add organic solvent, at acyclic acidic
Border or alkaline environment or directly heat lower continue reaction, reaction temperature is the reflux temperature of coordinative solvent system, intermediate VII take off
Water obtains [1-methyl-2-(7'-enanthic acid ester group)-5-the amino]-1H-benzimidazole such as Formula VIII or its salt, and reaction equation is as follows:
One or more in ruthenium, nickel, platinum, palladium of described catalyst；
One or more in methanol, ethanol, oxolane of described organic solvent；
(3) step (2) products therefrom VIII, in organic solvent with chloroacetate reaction, obtains [1-methyl-the 2-such as Formula IX
(7'-enanthic acid ester group)-5-N, N-bis-(2'-chloracetyl)]-1H-benzimidazole；Add reducing agent and continue reaction, obtain such as Formula X
Reduzate [1-methyl-2-(7'-enanthic acid ester group)-5-N, N-bis-(2'-chloroethyl)]-1H-benzimidazole, reaction temperature is
20～90 DEG C, reaction equation is as follows:
Described organic solvent is selected from oxolane, dichloromethane, dimethylformamide, in acetonitrile, diisopropyl ether, dioxane
Plant or several；
One or more in borine, borine-oxolane, lithium borohydride, sodium borohydride of described reducing agent；
(4) step (3) gained reduzate X, obtains intermediate X I, intermediate X I and O-(Pentamethylene oxide .-2-through hydrolysis
Base) azanol additive reaction in organic solvent obtains intermediate X II, and intermediate X II is reacted under sour environment and is obtained described step
Suddenly target compound I or its salt in (4), reaction scheme is as follows:
Described organic solvent one in oxolane, dichloromethane, dimethylformamide, acetonitrile, methanol, dioxane
Or it is several；
R in above-mentioned reaction equation is methyl, R1For C1-6Alkyl, phenyl, benzyl or phenethyl, X is Cl, Br, I or OH.
[1-methyl-2-(7'-hydroxamic acid in heptan base)-5-N, N-bis-(2'-chloroethyl)] the most according to claim 1-1H-
The synthetic method of benzimidazole, it is characterised in that raw material 2 in described step (1), 4-dinitroanilines is 2,4-bis-
Nitroaniline, mixes with suberic acid monoester or its acylate and adds to organic solvent, react, reaction temperature under alkaline environment
It is 60～150 DEG C, obtains intermediate 8-(2, the 4-dinitrophenyl) amino-8-oxo octanoic acid ester such as Formula IV；Addition methylates
Reagent continues reaction, obtains product 8-(2,4-dinitrophenyl) methylamino-8-oxo octanoic acid ester in described step (1), reaction
Formula is as follows:
Wherein R1For C1-6Alkyl, phenyl, benzyl or phenethyl, X is Cl, Br, I or OH；
Described organic solvent is selected from dimethylformamide, oxolane, ethyl acetate, dichloromethane, acetonitrile, toluene, dimethylbenzene
In one or more；
Described methylating reagent is selected from dimethyl sulfate, iodomethane or dimethyl sulfoxide；
[1-methyl-2-(7'-hydroxamic acid in heptan base)-5-N, N-bis-(2'-chloroethyl)] the most according to claim 2-1H-
The synthetic method of benzimidazole, it is characterised in that formulaMiddle X is OH, described 2,4-bis-
Nitroaniline and suberic acid monoester react the process preparing 8-(dinitrophenyl group) amino-8-oxo octanoic acid ester such as Formula IV
In, add coupling reaction reagent DMAP or 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate.
[1-methyl-2-(7'-hydroxamic acid in heptan base)-5-N, N-bis-(2'-chloroethyl)] the most according to claim 1 and 2-
The synthetic method of 1H-benzimidazole, it is characterised in that described step (1) i.e. raw material 2,4-dinitroanilines, with pungent
Monomethyl diester hybrid reaction obtains in the reaction of product V, and described reaction temperature is 100～150 DEG C, and organic solvent is acetonitrile or two
Toluene, methylating reagent is dimethyl sulfate, and the alkali added in reaction is potassium carbonate.
[1-methyl-2-(7'-hydroxamic acid in heptan base)-5-N, N-bis-(2'-chloroethyl)] the most according to claim 1-1H-
The synthetic method of benzimidazole, it is characterised in that after described step (2) filters catalyst, intermediate VII quilt under sour environment
Dehydrogenation cyclization obtains the phase of product [1-methyl-2-(7'-enanthic acid ester group)-5-the amino]-1H-benzimidazole of described step (2)
Answer salt form.
[1-methyl-2-(7'-hydroxamic acid in heptan base)-5-N, N-bis-(2'-chloroethyl)] the most according to claim 1-1H-
The synthetic method of benzimidazole, it is characterised in that obtain intermediate after described step (2) the i.e. hydrogenated reduction of product V cyclization
In the reaction of VII, described reaction pressure is 2.5～7 normal atmospheres, and catalyst is palladium content 5～the palladium carbon of 10%, organic
Solvent is methanol, and the acid added in reaction is concentrated hydrochloric acid.
[1-methyl-2-(7'-hydroxamic acid in heptan base)-5-N, N-bis-(2'-chloroethyl)] the most according to claim 1-1H-
The synthetic method of benzimidazole, it is characterised in that described step (3) i.e. cyclised products VIII and chloroacetate reaction, add reducing agent
Obtaining in the reaction of product X after reduction, described reaction temperature is 40～90 DEG C, and organic solvent is oxolane, and reducing agent is boron
Alkane-oxolane.
[1-methyl-2-(7'-hydroxamic acid in heptan base)-5-N, N-bis-(2'-chloroethyl)] the most according to claim 1-1H-
The synthetic method of benzimidazole, it is characterised in that described reduzate X obtains intermediate X I, hydrolysis bag through hydrolysis
Including acid hydrolysis or alkaline hydrolysis, wherein during acid adding, hydrolysing agent is concentrated hydrochloric acid, and hydrolysis temperature is 80～100 DEG C, water when adding alkali
Solution reagent is Lithium hydrate, and hydrolysis temperature is 0～15 DEG C.
9. there is the compound of following structure:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110275348.8A CN102993102B (en) | 2011-09-16 | 2011-09-16 | The synthetic method of [1-methyl-2-(hydroxamic acid base in 7 '-heptan)-5-N, N-bis-(2 '-chloroethyl)]-1H-benzimidazole |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110275348.8A CN102993102B (en) | 2011-09-16 | 2011-09-16 | The synthetic method of [1-methyl-2-(hydroxamic acid base in 7 '-heptan)-5-N, N-bis-(2 '-chloroethyl)]-1H-benzimidazole |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102993102A CN102993102A (en) | 2013-03-27 |
| CN102993102B true CN102993102B (en) | 2016-08-24 |
Family
ID=47922278
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201110275348.8A Active CN102993102B (en) | 2011-09-16 | 2011-09-16 | The synthetic method of [1-methyl-2-(hydroxamic acid base in 7 '-heptan)-5-N, N-bis-(2 '-chloroethyl)]-1H-benzimidazole |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102993102B (en) |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2911427T3 (en) * | 2011-09-18 | 2022-05-19 | Euro Celtique Sa | Pharmaceutical composition comprising an HDAC inhibitor and a cyclopolysaccharide |
| AR092790A1 (en) | 2012-02-01 | 2015-05-06 | Euro Celtique Sa | BENCIMIDAZOLIC DERIVATIVES OF HYDROXAMIC ACID |
| GB201409471D0 (en) | 2014-05-28 | 2014-07-09 | Euro Celtique Sa | Pharmaceutical composition |
| GB201409488D0 (en) | 2014-05-28 | 2014-07-09 | Euro Celtique Sa | Pharmaceutical composition |
| GB201409485D0 (en) | 2014-05-28 | 2014-07-09 | Euro Celtique Sa | Pharmaceutical composition |
| US11266631B2 (en) | 2016-10-11 | 2022-03-08 | Purdue Pharmaceutical Products L.P. | Hodgkin lymphoma therapy |
| GB201709405D0 (en) | 2017-06-13 | 2017-07-26 | Euro Celtique Sa | Compounds for treating ovarian cancer |
| GB201709403D0 (en) | 2017-06-13 | 2017-07-26 | Euro Celtique Sa | Compounds for treating sarcoma |
| GB201709402D0 (en) | 2017-06-13 | 2017-07-26 | Euro Celtique Sa | Compounds for treating t-pll |
| GB201709406D0 (en) | 2017-06-13 | 2017-07-26 | Euro-Cletique S A | Compounds for treating TNBC |
| CN109516957A (en) * | 2018-08-03 | 2019-03-26 | 杭州梯诺医药科技有限公司 | NL-101 polymorphic and preparation method thereof |
| CN112209884B (en) * | 2019-07-12 | 2022-11-11 | 杭州梯诺医药科技有限公司 | 1-H benzimidazole derivative, preparation method and application thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102177140A (en) * | 2008-10-08 | 2011-09-07 | 赛福伦公司 | Processes for the preparation of bendamustine |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ME02254B (en) * | 2009-01-23 | 2015-12-31 | Euro Celtique Sa | Hydroxamic acid derivatives |
-
2011
- 2011-09-16 CN CN201110275348.8A patent/CN102993102B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102177140A (en) * | 2008-10-08 | 2011-09-07 | 赛福伦公司 | Processes for the preparation of bendamustine |
Non-Patent Citations (2)
| Title |
|---|
| 4-二甲氨基吡啶的合成及其催化的有机反应;廖联安,等.;《合成化学》;19951231;第3卷(第3期);全文 * |
| The Synthesis of N-Hydroxy-N’-phenyloctanediamide and Its Inhibitory Effect on Proliferation of AXC Rat Prostate Cancer Cells;John C Stowell, et al.;《Journal of Medicinal Chemistry》;19951231;第38卷;第1411页倒数第4-14行 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102993102A (en) | 2013-03-27 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102993102B (en) | The synthetic method of [1-methyl-2-(hydroxamic acid base in 7 '-heptan)-5-N, N-bis-(2 '-chloroethyl)]-1H-benzimidazole | |
| US20230057608A1 (en) | Methods for the synthesis of activated ethylfumarates and their use as intermediates | |
| CN111423452B (en) | Intermediate of Rayleigh Lu Geli and preparation method and application thereof | |
| CN113429423B (en) | Rugoside intermediate and preparation method thereof | |
| CN104910150B (en) | Process for the manufacture of pharmaceutically active compounds | |
| CN104130261A (en) | Idelalisib synthetic method | |
| CN101346355A (en) | Improved process for the preparation of the salts of 4-(benzimidazolylmethylamino)-benzamides | |
| ES2769255T3 (en) | Methods for making protein deacetylase inhibitors | |
| EP3280721B1 (en) | Process for preparation of nitrogen mustard derivatives | |
| CN102267995A (en) | Method for preparing diazaspiro compound | |
| CN111320552A (en) | Preparation method of enzalutamide intermediate | |
| CN107118161A (en) | The synthetic method of the carboxylic acid of 2 n-propyl, 4 tolimidazole 6 | |
| CN107698538A (en) | The intermediate 3 of roxatidine acetate hydrochloride（1 piperidine methyl）The new preparation method of phenol | |
| CN103922986B (en) | Vildagliptin, vildagliptin analogues and vildagliptin intermediate, and preparation methods of three and application | |
| CN101891650A (en) | Production method of N-substituted carbamate | |
| CN102603609A (en) | Method for synthesizing D-isoglutamine-D-tryptophan | |
| CN104876930B (en) | The method of synthetically prepared compound | |
| CN108658851B (en) | 2-chloro-3-methyl-6-acylaminopyridine and preparation method and application thereof | |
| EP1541582A1 (en) | Process for producing indolopyrrolocarbazole derivative | |
| CN115466219A (en) | Preparation method of 1- [3- (2-amino-4-ethyl-1H-imidazole-5-yl) propyl ] guanidine | |
| CN108997316A (en) | A kind of preparation process of dabigatran etcxilate | |
| NZ736564B2 (en) | Process for preparation of nitrogen mustard derivatives |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C53 | Correction of patent for invention or patent application | ||
| CB02 | Change of applicant information |
Address after: 311100 No. 36, Linping Avenue, Yuhang economic and Technological Development Zone, Zhejiang, Hangzhou Applicant after: Hangzhou Minsheng Pharmaceutical Co., Ltd. Address before: 310011, No. 108 Tong Road, Yuhang, Zhejiang, Hangzhou (high tech Zone) Applicant before: Hangzhou Minsheng Pharmaceutical Co., Ltd. |
|
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20180515 Address after: 310052 201, room 1, 658 Binan Road, Changhe street, Binjiang District, Hangzhou, Zhejiang. Patentee after: Hangzhou stno medical science and Technology Co., Ltd. Address before: 311100 Linping Avenue, Yuhang economic and Technological Development Zone, Hangzhou, Zhejiang 36 Patentee before: Hangzhou Minsheng Pharmaceutical Co., Ltd. |