CN106467513A - A kind of synthetic method preparing Niraparib - Google Patents
A kind of synthetic method preparing Niraparib Download PDFInfo
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- C07—ORGANIC CHEMISTRY
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
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Abstract
A kind of synthetic method preparing Niraparib, the method includes initiation material 3 methyl 2 nitrobenzoic acid and obtains, through esterification, 3 methyl hydroformylations, schiff base reaction, cyclisation, amidatioon, de- BOC, chiral separation, the optical voidness Niraparib that purity reaches more than 91%.The inventive method is easy, and, it is easy to operate, equipment requirements are few, are a method which be suitable for industrial production for efficiency high.
Description
Technical field
The present invention relates to the synthesis of cancer therapy drug is and in particular to prepare the synthetic method of Niraparib.
Background technology
Niraparib chemical name is 2- [4- ((3S) -3- piperidyl) phenyl] -2H- indazole -7- Methanamide, is a kind of
Oral Poly ADP-ribose polymerase (PARP) inhibitor, can suppress the reparation to DNA damage for the cell.For with BRCA gene
For the cancerous cell of mutation, if PARP activity is suppressed further, a large amount of DNA will be produced during these cell divisions and damage
Wound, leads to cancer cell death.And normal cell because also BRCA exist, do not have PARP still can DNA plerosis, simply effect is poor
Some, but can survive.Here it is PARP inhibitor is as targeted drug, the reason selectivity kills BRCA mutated cancer cells.
Niraparib is applied to the cancer of BRCA1/2 gene mutation, such as ovarian cancer and breast carcinoma etc., by biotech company of the U.S.
Tesaro researches and develops.Complete the III clinical trial phase that a key name is NOVA, Niraparib presents extremely good curative effect.
Carry in the group of BRCA mutation in sexual cell, be up to through the median of patient's progression free survival phase of Niraparib treatment
21 months, obtain notable prolongation than 5.5 months of matched group.
At present, in prior art, Preparation is included for the relevant patent documentation of the synthetic method of Niraparib
of pharmaceutically acceptable salts of (3S)-3-[4-[7-(aminocarbonyl)-2H-
indazol-2-yl]phenyl]piperidines as inhibitors of poly(ADP-ribose)polymerase
(PARP), Preparation of piperidinylphenylindazolylcarboxamide for use as poly
(ADP-ribose) polymerase inhibitors etc., discloses a pharmaceutical chemistry synthetic route and to Niraparib's
Discovery procedure has carried out detailed discussion.
This synthetic route with 3- methyl -2- nitrobenzoic acid as initiation material, by with methanol under conditions of acyl chlorides ester
Change and obtain compound A, A is heated to reflux 12 hours in the CCl4 solution with NBS for the benzoyl peroxide, and bromination obtains compound B.B with
Acetonitrile and the oxidation of N-methylmorpholine-N- oxide water solution obtain compound C.The compound C and tert-butyl group -3- (4- aminophenyl)
Piperidines -1- carboxylic acid tert-butyl ester is stirred at reflux in ethanol solution and obtains compound D.Compound D and Hydrazoic acid,sodium salt and DMF mixture
Reaction, cyclization formed intermediate E .. compound E be passed through in methanol solution 60 DEG C of NH3 heating acylated intermediate F. compound
F adds hydrochloric acid in ethyl acetate with dioxane solution, sloughs BOC group and obtains intermediate G, through Chiralpak AS-H positive
Chiral chromatographic column splits and obtains target compound S type conformer Niraparib.This synthetic route is longer, uses
Chiralpak AS-H positive chiral chromatographic column split Niraparib is difficult to realize large-scale commercial production, and react in
Employ the raw material of the unstable and difficult post processing such as Hydrazoic acid,sodium salt, limit industrialization safety in production.
Content of the invention
In order to overcome the above-mentioned deficiencies of the prior art, the purpose of the present invention is to improve one kind to prepare PARP inhibitor
The synthetic method of Niraparib, route is novel, obtains multiple brand-new intermediate in building-up process, and the property of intermediate
Stable, easy and simple to handle, it is easy to accomplish industrialized great production.
To achieve these goals, the present invention to realize process as follows：
A kind of synthetic method preparing Niraparib is it is characterised in that its synthetic route is as follows：
Wherein compound (I) is Niraparib；
The following specifically describes synthesis step：
1) structure of intermediate (1) is as follows：Synthesis step includes initiation materialHeat under the catalytic action of concentrated sulphuric acid with methanol, occur esterification to form intermediate (1)；
2) structure of intermediate (2) is as follows：Synthesis step includes：Intermediate (1) is in 65% nitre
Under the acid condition of acid, benzyl is oxidized to by aldehyde radical by activated manganese dioxide (AMD) selectivity；
3) structure of intermediate (3) is as follows：Synthesis step includes：Intermediate (2)With compoundSolvent is done with methanol, adds reaction of sodium bicarbonate to form intermediate (3)；
4) structure of intermediate (4) is as follows：Synthesis step includes：Intermediate (3) and Asia
Triethyl phosphate is heated to reflux cyclization in 24 hours under conditions of 92 DEG C and forms indazole ring intermediate (4)；
5) structure of intermediate (5) is as followsSynthesis step includes：Intermediate (4) is in methanol
In the presence of sodium, Methanamide, methyl ester ammonification forms amide.
6) structure of intermediate (6) is as followsSynthesis step includes：Intermediate (5) is in dichloromethane
(DCM), in, react de- BOC base with trifluoroacetic acid；
7) method that Niraparib racemization intermediate 6 obtains compound (I) Niraparib, compound (I) are split
Niraparib structure is：Splitting step includes：Niraparib racemization intermediate 6 is dissolved in organic molten
Backflow dissolving in agent, adds N- acetyl group-L-Leu, crystallize of lowering the temperature, and separates solid crystal, obtains Niraparib.N- acetyl
Base-L-Leu salt, is dissolved in water, and hydro-oxidation sodium solution alkalizes, and then adds ethyl acetate extraction, washs,
It is drying to obtain compound (I) Niraparib.
Further describe in detail：
1) preparation of intermediate (1) (preparation of 3- methyl -2- nitrobenzene methyl)：Can be with adding under sulphuric acid catalysis
Hot reflux is reacted, or carboxylic acid generation acyl chlorides is reacted with alcohol again, can also be esterified, preferably use here in the presence of thionyl chloride
Sulphuric acid catalysis are heated to reflux being esterified, and the temperature of described esterification is 58 DEG C about；
2) under conditions of 40 DEG C, 65% nitric acid is added in intermediate (1), is urged by AMD (activated manganese dioxide)
Change oxidation intermediates (1) and form intermediate (2), AMD oxidation susceptibility is gentle, can optionally aoxidize benzyl is aldehyde radical, and
Other functional groups are not produced with impact it is achieved that methyl oxidation is aldehyde radical by a step；
3) intermediate (2) and the compound containing BOC base make solvent with methanol, add NaHCO3 to react 2 hours, you can be formed
Niraparib intermediate (3), can also use tetra-acetylated titanium, or tetra isopropyl titanate make solvent it is contemplated that solvent cost and
The complexity sloughed, preferably methanol make solvent；
4) NSC 5284 is added in intermediate (3), being heated to reflux 24h at 92 DEG C can ring synthetic intermediate
(4) indazole ring；
5) form the acyl in Niraparib intermediate (5) after intermediate (4) ammonolysis in the presence of Feldalat NM, Methanamide
Amine structure；
6) the de- BOC protection group of intermediate (5) obtains intermediate (6)；Solvent is made with DCM (dichloromethane), material mole
Than for intermediate：DCM：Trifluoracetic acid=1:5:1, about 3 hour reaction is stirred at room temperature completely, is evaporated and obtains final product Niraparib racemization
Intermediate (6)；
7) Niraparib racemization intermediate (6) obtains compound (I) Niraparib through chemical resolution：By racemization intermediate
(6) it is dissolved in backflow dissolving in organic solvent, add N- acetyl group-L-Leu, crystallize of lowering the temperature, separate solid crystal, obtain
Niraparib.N- acetyl group-L-Leu salt, is dissolved in water, and hydro-oxidation sodium solution alkalizes, and then adds second
Acetoacetic ester extracts, washing, is drying to obtain compound (I) Niraparib.
The described organic solvent described in racemization intermediate (6) splitting step be methanol, ethanol, acetone, ethyl acetate or
Its mixture, organic solvent is 8～18 with the mass ratio of intermediate (6):1.
The described N- acetyl group-L-Leu described in racemization intermediate (6) splitting step and the mass ratio of intermediate (6)
For 0.6～6:1.
The invention has the beneficial effects as follows：
1) initiation material 3- methyl -2 nitrobenzoic acid that the present invention adopts is commonly used for organic drug synthesis field
Raw material, low price and also be readily obtained；
2) synthesis step of the present invention is simple, and operating condition is easy to control；
3) present invention in each intermediate link only with such as：Extraction, be dried, filter, crystallization and the operation such as recrystallization
Method, post processing is simple and convenient, is easier to realize large-scale production；
4) route of the present invention is novel, the solvent used in building-up process and the stable in properties of catalyst it is easy to product
Thing separates, easy and simple to handle, efficiency high, it is easy to accomplish industrialized great production.
Brief description
Fig. 1 is Niraparib HPLC chromatogram.
Specific embodiment
With reference to embodiments the present invention is further discussed below, but the present invention is not limited to following examples.
Embodiment 1
Niraparib intermediate 1Synthesis
The synthesis of Niraparib intermediate 1 is carried out in two steps, the first step (esterification)：By 3- methyl -2- nitrobenzoyl
Acid and methanol press n (3- methyl -2- nitrobenzoic acid):N (methanol)=1：5 ratio, that is, take 182g3- methyl -2- nitrobenzoyl
Acid, the methanol of 160.2g is placed in the triangular flask with reflux, slow heating, treats that 3- methyl -2- nitrobenzoic acid is complete
After being dissolved in methanol, add the concentrated sulphuric acid of 6mL, rise high-temperature and reacted to 58 DEG C, product is 3- methyl -2- nitro this formic acid first
Ester (Niraparib intermediate 1) and water.The Niraparib intermediate 1 generating carries out second step (refined extraction)：Esterification
After finishing, after the temperature of question response liquid is down to room temperature, adjusts the PH of solution to neutral with sodium bicarbonate, extraction flask separates oil phase
Layer, the sodium bicarbonate solution cyclic washing with 0.1kg/L is extremely neutral, and obtaining Niraparib intermediate 1 with anhydrous sodium sulfate drying is
160.04g, yield is 82.2%.
1HNMR(300MHz,DMSO-d6)δ(ppm):8.12(1H,d,7.2Hz),7.70(1H,d,7.2Hz),7.69
(1H,t),3.89(3H,s),2.34(3H,s)；13CNMR(75MHz,DMSO-d6)δ(ppm):164.3,150.3,137.0,
134.6,132.0,124.4,117.7,51.5,18.3；HRMS(ESI)for(M+H)+:calcd:195.05,found:
196.04
Niraparib intermediate 2Synthesis
Take Niraparib intermediate 1 (0.88mol) 160g in having in the triangular flask of backflow and agitating device, add
230g (2.64mol) AMD (activated manganese dioxide), stirring is lower to add the nitric acid (0.6mol) of 55mL65% to be slowly heated to 40
DEG C, flow back 5-7h. filtered while hot, separates oil phase layer after standing, and the sodium bicarbonate solution cyclic washing with 0.1kg/L is extremely neutral,
Standby with anhydrous sodium sulfate drying, obtaining Niraparib intermediate 2 is 130.98g, and yield is 66.4%.
1HNMR(300MHz,DMSO-d6)δ(ppm):10.36(1H,s),8.59(1H,d,7.5Hz),8.36(1H,d,
7.5Hz),8.03(1H,t),3.89(3H,s)；13CNMR(75MHz,DMSO-d6)δ(ppm):188.2,164.3,150.8,
135.1,133.2,131.1,118.3,51.5；
HRMS(ESI)for(M+H)+:calcd:209.03,found:210.04
Niraparib intermediate 3Synthesis
Take Niraparib intermediate 2 (0.4mol) 89.6g, add in 100ml methanol solution, be sufficiently mixed, be subsequently adding
116.5g (0.4mol) tert-butyl group -3- (4- amino) Phenylpiperidine -1- t-butyl formate, half acetic acid is catalyst, 18g
(0.2mol) sodium bicarbonate, be heated to 40 DEG C backflow 2h, be cooled to room temperature after crystal precipitation after sucking filtration, with washing with alcohol twice after
With anhydrous magnesium sulfate dry 169g (0.34mol) Niraparib intermediate 3, yield be 85%.
1HNMR(300MHz,DMSO-d6)δ(ppm):8.64(1H,s),8.47(1H,d,7.3Hz),8.30(1H,d,
7.3Hz),8.02(1H,t,7.5Hz),7.30(2H,,q,7.6Hz),7.25(2H,q,7.6Hz)3.89(3H,s)3.62(2H,
d,7.5Hz),3.34(2H,t,7.5Hz),2.78(1H,m)1.78(2H,q)1.48(2H,m)1.38(9,s)；13CNMR
(75MHz,DMSO-d6)δ(ppm):164.3,160.0,143.2,150.1,149.2,137.6,134.6,129.6,128.3,
122.1,117.9,79.8,57.0,51.5,49.0,40.5,30.5,28.4,22.7；
HRMS(ESI)for(M+H)+:calcd:467.21,found:468.21
Niraparib intermediate 4Synthesis.
Take Niraparib intermediate 3 (0.2mol) 100g in round-bottomed flask, by 0.04 (mol) 6.65g phosphorous triethylenetetraminehexaacetic acid
Ester adds in Niraparib intermediate 3, is heated to 92 DEG C of backflow 24h, filtered while hot, cooling crystallization, 40 DEG C are vacuum dried 4h,
Obtain 86.7g Niraparib intermediate 4, yield is 90%.
1H-NMR(300MHz,DMSO-d6)(ppm)δ:8.51 (1H, s), 8.13 (1H, d, J=7.1Hz), 7.95 (1H,
D), 7.91 (2H, d, J=8.4Hz), 7.39 (2H, d, J=8.4Hz), 7.18 (1H, t, J=7.1Hz), 4.30-4.10 (2H,
m),4.00(3H,s),2.85-2.70(3H,m),2.11-2.03(1H,m),1.83-1.75(1H,m),1.73-1.53(2H,
m),1.48(9H,s).
13CNMR(75MHz,DMSO-d6)δ(ppm):167.1,153.2,145.6,136.9,128.7,124.3,120.6,
112.0,79.8,57.0,51.5,49.0,40.5,30.5,28.4,22.7；HRMS(ESI)for(M+H)+:calcd:
435.22,found:436.22
Niraparib intermediate 5Synthesis.
At 0 DEG C, 17.2g (41mmol) Niraparib intermediate 4 is dissolved in 100mL dry DMF, adds in this solution
13mL (328mmol) Methanamide, 3.3g (62mmol) Feldalat NM, are warming up to 40 DEG C of reaction 3.5h.Reactant liquor is cooled to room temperature,
It is poured in 400mL water, stirs 1h, sucking filtration, be dried, (theoretical yield is to obtain Niraparib intermediate 5 crude product 17.23g
13.78g), yield is 87%.Under room temperature, Niraparib intermediate 5 crude product 10.0g is added to 80mL dioxane-water (body
Long-pending compare 8: 1) mixed solvent in, be warming up to 101 DEG C, add 0.2g (mass fraction 2%) activated carbon after solid is entirely molten, continue back
Stream 0.5h, sucking filtration while hot, filtrate is cooled to 0 DEG C, standing 2h (precipitation white needle-like crystals), and sucking filtration is dried, and separates out crystal
(Niraparib intermediate 5).
1H-NMR(300MHz,DMSO-d6)(ppm)δ:9.04 (1H, br.s), 8.51 (1H, s), 8.31 (1H, d, J=
8.3Hz), 7.91 (1H, d, J=8.3Hz), 7.84 (2H, d, J=8.2Hz), 7.42 (2H, d, J=8.2Hz), 7.31-7.22
(1H,m),5.95(1H,br.s),4.40-4.05(2H,m),2.90-2.70(3H,m),2.15-2.00(1H,m),1.85-
1.75(1H,m),1.75-1.50(2H,m),1.48(9H,s).13CNMR(75MHz,DMSO-d6)δ(ppm):168.0,153.2,
143.2,136.9,128.7,126.7,125.0,124.1,120.8,115.0,79.8,57.0,49.0,30.5,40.5,
28.4,22.7,HRMS(ESI)for(M+H)+:calcd:420.22,found:421.22.
Niraparib intermediate 6Synthesis
18g Niraparib intermediate 5 (42mmol) is added in 180ml dichloromethane, after being sufficiently mixed, gradually drips
Plus trifluoroacetic acid solution 45mL, stir 20h, add 70mL sodium hydrate aqueous solution, stratification, separate organic faciess, anhydrous sulfur
Sour sodium obtains 11.2g Niraparib intermediate 6 after being dried, and molar yield is 83.33%.
1H-NMR(300MHz,DMSO-d6)(ppm)δ:8.52 (1H, s), 8.17 (1H, br, d), 8.03 (1H, d, J=
7.2Hz), 7.66 (1H, q, J=8.4Hz), 7.54 (2H, t), 7.50 (2H, br., s), 7.30 (2H, d, J=8.4Hz),
3.15-2.90(2H,d),2.78(1H,m),2.76-2.73(2H,t),2.0(1H,m),1.92-1.67(2H,q),1.53-
1.43(2H,m).13CNMR(75MHz,DMSO-d6)δ(ppm):168.0,143.2,136.9,128.7,126.7,124.1,
120.8,115.0,52.4,48.6,43.3,30.5,25.5.HRMS(ESI)for(M+H)+:calcd:320.16,found:
321.16.
NiraparibSynthesis
100g Niraparib intermediate 6 is added in 1000ml methanol, adds 330gN- acetyl group-L-Leu to add
System, to 70 DEG C of back flow reaction 1h, is then cooled to -10～0 DEG C of crystallize, is filtrated to get solid by heat；Solid is pure with 200ml
Crystal's system, obtains the N- acetyl group-L-Leu salt 62.19g of Niraparib, molar yield 42.3%.
The N- acetyl group of Niraparib-L-Leu salt 4.5g is added in 22.5ml pure water, then room temperature water bath condition
Lower addition sodium hydroxide solution 1.3g, is subsequently adding ethyl acetate 45.0ml, is stirred at room temperature to clarification.Divide liquid, aqueous phase is used again
45.0ml ethyl acetate extracts, and merges organic faciess；Washed with water 15ml and saturated nacl aqueous solution 15ml successively, use anhydrous slufuric acid
Sodium filters after being dried, and filtrate is concentrated to dryness, and solid is taken out and obtains Niraparib 2.81g, this step reaction yield after forced air drying
For 91.2%, overall yield of reaction is 11.68%.Measuring Niraparib purity through HPLC is 91.81% (chromatogram following Fig. 1 institute
Show), using Daicel companyAD-3 150mm × 2.1mm chiral column records ee value for 99.5%.
1H-NMR(300MHz,DMSO-d6)(ppm)δ:8.52 (1H, s), 8.17 (1H, br, d), 8.03 (1H, d, J=
7.2Hz), 7.66 (1H, q, J=8.4Hz), 7.54 (2H, t), 7.50 (2H, br.s), 7.30 (2H, d, J=8.4Hz), 3.15-
2.90(2H,d),2.78(1H,m),2.76-2.73(2H,t),2.0(1H,m),1.92-1.67(2H,q),1.53-1.43(2H,
m).13CNMR(75MHz,DMSO-d6)
(ppm):168.0,143.2,136.9,128.7,126.7,125.0,124.1,115.0,52.4,43.3,48.6,
30.5,25.5,HRMS(ESI)for(M+H)+:calcd:320.16,found:321.16.
Claims (10)
1. a kind of synthetic method preparing Niraparib is it is characterised in that its synthetic route is as follows：
Wherein compound (I) is Niraparib.
2. a kind of synthetic method preparing Niraparib according to claim 1 is it is characterised in that the structure of intermediate 1
As follows：Synthesis step includes initiation materialWith methanol concentrated sulphuric acid catalysis
Effect is lower to heat, and occurs esterification to form intermediate (1).
3. a kind of synthetic method preparing Niraparib according to claim 1 is it is characterised in that the knot of intermediate (2)
Structure is as follows：Synthesis step includes：Intermediate (1) under the acid condition of 65% nitric acid, by activity two
Benzyl is oxidized to aldehyde radical by manganese oxide (AMD) selectivity.
4. a kind of synthetic method preparing Niraparib according to claim 1 is it is characterised in that the knot of intermediate (3)
Structure is as follows：Synthesis step includes：Intermediate (2)With compoundSolvent is done with methanol, adds reaction of sodium bicarbonate to form intermediate (3).
5. a kind of synthetic method preparing Niraparib according to claim 1 is it is characterised in that the structure of intermediate 4
As follows：Synthesis step includes：Intermediate 3 and NSC 5284 heat under conditions of 92 DEG C
Backflow cyclization in 24 hours forms indazole ring intermediate (4).
6. a kind of synthetic method preparing Niraparib according to claim 1 is it is characterised in that the knot of intermediate (5)
Structure is as followsSynthesis step includes：Intermediate 4 in the presence of Feldalat NM, Methanamide, methyl ester ammonification
Form amide.
7. a kind of synthetic method preparing Niraparib according to claim 1 is it is characterised in that the structure of intermediate 6
As followsSynthesis step includes：Intermediate 5, in dichloromethane (DCM), reacts de- BOC with trifluoroacetic acid
Base.
8. a kind of synthetic method preparing Niraparib according to claim 1 is it is characterised in that split Niraparib
The method that racemization intermediate (6) obtains compound (I) Niraparib, compound (I) Niraparib structure is：Splitting step includes：Niraparib racemization intermediate (6) is dissolved in backflow dissolving in organic solvent, plus
Enter N- acetyl group-L-Leu, crystallize of lowering the temperature, separate solid crystal, obtain Niraparib.N- acetyl group-L-Leu salt,
It is dissolved in water, hydro-oxidation sodium solution alkalizes, then add ethyl acetate extraction, washing, be drying to obtain compound
(I)Niraparib.
9. a kind of synthetic method preparing Niraparib according to claim 1 is it is characterised in that racemization intermediate (6)
Organic solvent described in splitting step is methanol, ethanol, acetone, ethyl acetate or its mixture, organic solvent and intermediate (6)
Mass ratio be 8～18:1.
10. a kind of synthetic method preparing Niraparib according to claim 1 is it is characterised in that racemization intermediate
(6) the N- acetyl group-L-Leu described in splitting step and the mass ratio of intermediate (6) are 0.6～6:1.
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| CN110156751A (en) * | 2019-05-28 | 2019-08-23 | 江苏食品药品职业技术学院 | A kind of new method preparing Ni Lapani and its intermediate |
| CN110407704A (en) * | 2019-08-19 | 2019-11-05 | 常州沃腾化工科技有限公司 | A kind of synthetic method of 3- formoxyl -2- nitrobenzene methyl |
| JP2020536870A (en) * | 2017-10-05 | 2020-12-17 | バイオジェン インコーポレイテッド | Method for preparing alphacarboxamide pyrrolidine derivative |
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| CN106632244A (en) * | 2016-09-30 | 2017-05-10 | 陕西科技大学 | A novel synthetic method for preparing an anticancer medicine Niraparib |
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| GB0700432D0 (en) * | 2007-01-10 | 2007-02-21 | Angeletti P Ist Richerche Bio | Therapeutic compounds |
| CN106632244A (en) * | 2016-09-30 | 2017-05-10 | 陕西科技大学 | A novel synthetic method for preparing an anticancer medicine Niraparib |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2020536870A (en) * | 2017-10-05 | 2020-12-17 | バイオジェン インコーポレイテッド | Method for preparing alphacarboxamide pyrrolidine derivative |
| CN112153968A (en) * | 2017-10-05 | 2020-12-29 | 生物基因公司 | Process for the preparation of alpha-carboxamide pyrrolidine derivatives |
| CN110156751A (en) * | 2019-05-28 | 2019-08-23 | 江苏食品药品职业技术学院 | A kind of new method preparing Ni Lapani and its intermediate |
| CN110407704A (en) * | 2019-08-19 | 2019-11-05 | 常州沃腾化工科技有限公司 | A kind of synthetic method of 3- formoxyl -2- nitrobenzene methyl |
| CN110407704B (en) * | 2019-08-19 | 2022-05-17 | 常州沃腾化工科技有限公司 | Synthetic method of 3-formyl-2-nitrobenzoic acid methyl ester |
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