CN110183367A - A kind of synthetic method of (3R, 4S) -1- benzyloxycarbonyl group -4- N-ethyl pyrrole N -3- carboxylic acid suitable for industrialization - Google Patents

A kind of synthetic method of (3R, 4S) -1- benzyloxycarbonyl group -4- N-ethyl pyrrole N -3- carboxylic acid suitable for industrialization Download PDF

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CN110183367A
CN110183367A CN201910498948.7A CN201910498948A CN110183367A CN 110183367 A CN110183367 A CN 110183367A CN 201910498948 A CN201910498948 A CN 201910498948A CN 110183367 A CN110183367 A CN 110183367A
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acid
ethyl
compound
benzyloxycarbonyl group
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周文斌
杨元明
王正喜
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Nanjing New Enzyme Pharmaceutical Technology Co Ltd
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Nanjing New Enzyme Pharmaceutical Technology Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

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  • Plural Heterocyclic Compounds (AREA)
  • Pyrrole Compounds (AREA)

Abstract

The invention discloses a kind of (3R suitable for industrialization, 4S) the synthetic method of -1- benzyloxycarbonyl group -4- N-ethyl pyrrole N -3- carboxylic acid, it include: to prepare intermediate condensation product through being condensed ring closure reaction under acid catalysis in a solvent using valerylene acid esters and N- methoxy-N- (trimethylsilylmethyl) benzyl amine as starting material；After ethyl chloroformate is added in intermediate; reaction obtains another intermediate; continue and benzyl chloroformate through acylation reaction prepares N protection midbody products; after ester hydrolysis reaction; with hydrogen through asymmetric reduction reaction; obtain (3R, 4S) -1- benzyloxycarbonyl group -4- N-ethyl pyrrole N -3- carboxylic acid.The present invention is reacted by five steps, purity and all higher (3R of yield are obtained, 4S) -1- benzyloxycarbonyl group -4- N-ethyl pyrrole N -3- carboxylic acid solves the problems, such as that quality in the prior art and yield are difficult to control, and sufficient raw material midbody is provided for Buddhist nun to synthesize black pa.

Description

A kind of (3R, 4S) -1- benzyloxycarbonyl group -4- N-ethyl pyrrole N -3- carboxylic suitable for industrialization The synthetic method of acid
Technical field
The present invention relates to a kind of conjunctions of (3R, 4S) -1- benzyloxycarbonyl group -4- N-ethyl pyrrole N -3- carboxylic acid suitable for industrialization At method, belong to chipal compounds synthesis technical field.
Background technique
JAK inhibitor alternative inhibits JAK kinases, blocks JAK/STAT access.JAK-STAT signal path is The signal transduction pathway that one of discovered in recent years is stimulated by cell factor participates in the proliferation of cell, differentiation, apoptosis and immune Many important biological processes such as adjusting.JAK is the target spot that industry is expected extensively.The support method of current existing Pfizer is replaced Buddhist nun is granted for treating rheumatoid arthritis, and sales volume reached 9.27 hundred million dollars in 2016.Novartis/Incyte Ruxolitinib(Luso replaces Buddhist nun) it is granted for treating myelofibrosis, polycythemia vera, global marketing volume in 2016 Also 14.34 hundred million dollars have been reached.
The new drug crow pa of AbbVie company is a kind of new oral selection for Buddhist nun (upadacitinib, code name ABT-494) Property JAK-1 inhibitor, treatment rheumatoid arthritis, psoriatic arthritis the III phase study it is in progress.In addition, Upadacitinib is also exploited for treatment Crohn disease, ulcerative enteritis and mandatory rachitis.On September 7th, 2017, AbbVie announces upadacitinib (ABT-494) treatment the random of atopic dermatitis, placebo, dosage range IIb research is reached home, and black pa shows fabulous effect for each dosage group clinical trial of Buddhist nun as the result is shown, which will be to crow Pa pushes further clinical trial to for Buddhist nun or great positive effect is played in listing., it is expected that black pa will have for Buddhist nun it is wide Market value, black pa will also have wide industrial value for Buddhist nun's bulk pharmaceutical chemicals.
Black pa is the hand-type heterocyclic compound containing two chiral centres for Buddhist nun's bulk pharmaceutical chemicals, and synthesis difficulty is very big.The website MCD is aobvious Show that maximum 25mg specification crow pa reaches 1620 U.S. dollars for Buddhist nun's compound price.Document report crow pa is economic cooperation for the synthetic route of Buddhist nun It has no progeny at two pieces and is no less than the reaction synthesis of 4 steps again.Wherein, hand-type segment compound is the key that technique and its synthesis Difficult point, integrated artistic and final products property to the compound play conclusive influence, and black pa is reported for Buddhist nun and closed It is as follows at route:
Hand-type segment compound prior art reports that yield is lower (total recovery is less than 15%), and technique is main to hand-type Pureness control It is repeatedly split after raceme or process route is too long, separate step severe reaction conditions, technical process by preparing There is the unfriendly condition of environment simultaneously.How technique entirety yield is improved under conditions of guaranteeing that hand-type purity is greater than 99%, shorten work Skill step reduces process costs, it will plays great influence to black pa for Buddhist nun's end product quality and price.
Patent CN104370909A//US2011/0311474A1//WO201106888A1 reports following route:
Using 2- alkynes ethyl valerate as starting material, alkene, then cyclization are become by hydrogenating reduction alkynes under Lindlar catalyst Racemization type intermediate is prepared, then CBZ protecting group on debenzylation, after hydrolysis, then passes through 3 times or more fractionations acquisition hand-type Purity is greater than 99% target product (3R, 4S) -1- benzyloxycarbonyl group -4- N-ethyl pyrrole N -3- carboxylic acid.The major defect of the technique is Synthesising racemation type precursor, then splits again, theoretical highest yield 50%, and net yield is about that 14.75%(is respectively walked open receipts by document Rate data combination resolution yield 100% calculates).Meanwhile product boiling point is extremely low after the reduction of the technique first step, subtracts at 25 DEG C of temperature Pressure is i.e. readily volatilized, largely effects on process recovery ratio, is unfavorable for industrialization production, while intermediate is ultraviolet after third step deprotection Absorption is weaker, is unfavorable for technical process HPLC tracking.
Patent WO2017066775A1 reports following synthetic route:
Report prepares final product using glycine ethyl ester derivative and ethyl acrylate as starting material, through the reaction of 6 steps.It should Process route major advantage is starting material economy, while synthesizing target product using asymmetric reduction, and single step hand-type yield has It significantly improves.Main shortcoming is that technique overall step is more, while separate step needs to control the reaction of anhydrous or anaerobic, The protecting group or catalyst used simultaneously is not easy removal in process influences Quality control of intermediates.The first step is reacted in industrialization It operates more demanding in amplification, is unfavorable for industrialization.
In conclusion avoiding above series of problem, (3R, 4S) -1- benzyloxycarbonyl group -4- second of suitable industrialization is developed Base pyrroles's -3- carboxylic acid synthesis technology is very necessary.
Summary of the invention
The technical problem to be solved by the present invention is to overcome prior art production technology complexity, defect rambunctious, provide A kind of synthetic method of (3R, 4S) -1- benzyloxycarbonyl group -4- N-ethyl pyrrole N -3- carboxylic acid of suitable industrialization.
Above-mentioned technical purpose of the invention has the technical scheme that
A kind of synthetic method of (3R, 4S) -1- benzyloxycarbonyl group -4- N-ethyl pyrrole N -3- carboxylic acid suitable for industrialization, feature It is, comprising the following steps:
S1, using valerylene acid esters and N- methoxy-N- (trimethylsilylmethyl) benzyl amine as starting material, in a solvent Intermediate condensation midbody product compound A, the structural formula of the compound A are prepared through being condensed ring closure reaction under acid catalysis Are as follows:
；
Compound A is added in solvent by S2, stirring, and after 0 ~ 5 DEG C of addition ethyl chloroformate, 1 ~ 2h is reacted at 20 ~ 25 DEG C Afterwards, alcohols solvent is added, the reaction was continued at 40 ~ 90 DEG C, obtains midbody product compound B, the structural formula of the compound B Are as follows:
；
S3, under the conditions of alkali, compound B prepares N protection intermediates through acylation reaction with benzyl chloroformate in a solvent and produces Compounds C, the structural formula of the compound C are as follows:
；
S4, under alkaline condition, compound C prepares midbody product compound D, describedization through ester hydrolysis reaction in a solvent Close the structural formula of object D are as follows:
；
Compound D is crystallized to obtain intermediate sterling through processing by S5, in a solvent, under the conditions of catalyst is existing, is passed through with hydrogen Asymmetric reduction reaction obtains (3R, 4S) -1- benzyloxycarbonyl group -4- N-ethyl pyrrole N -3- carboxylic acid, structural formula are as follows:
。
The synthetic route of (3R, 4S) -1- benzyloxycarbonyl group -4- N-ethyl pyrrole N -3- carboxylic acid are as follows:
By using above-mentioned technical proposal, five steps react (3R, the 4S) -1- benzyloxycarbonyl group -4- N-ethyl pyrrole N -3- carboxylic being prepared Acid, and easily-controlled reaction conditions.
Preferably, the valerylene acid esters in the S1 is valerylene acid methyl esters, valerylene acetoacetic ester or the tertiary fourth of valerylene acid One of ester；The R1For methyl, ethyl or tert-butyl；Solvent in the S1 be ethyl acetate, acetonitrile, toluene, acetone, Any one of methylene chloride, chloroform, 1,2- dichloroethanes or a combination thereof；Acid in the S1 is acetic acid, methyl sulphur Any one of acid, hydrochloric acid, sulfuric acid, trifluoroacetic acid, p-methyl benzenesulfonic acid or a combination thereof.
Preferably, valerylene acid esters and N- methoxy-N- (trimethylsilylmethyl) benzyl amine equivalent in the S1 Ratio is 0.8:1 ~ 1:2.
Preferably, the reaction temperature in the S1 is -5 ~ 50 DEG C.
Preferably, solvent is ethyl acetate, acetonitrile, toluene, acetone, methylene chloride, chloroform, 1,2- bis- in the S2 Any one of chloroethanes or a combination thereof；The equivalents ratio of compound A and ethyl chloroformate is (0.8 ~ 1) in the S2: (1 ~ 5)；Alcohols solvent is one of methanol, ethyl alcohol, isopropanol or combinations thereof in the S2.
Preferably, the solvent in the S3 is any in ethyl acetate, acetonitrile, toluene, acetone, methylene chloride and water Kind or a combination thereof；Alkali in the S3 is triethylamine, DBU, sodium carbonate, potassium carbonate, potassium hydroxide, any in saleratus Kind or combinations thereof；
The equivalents ratio that feeds intake of the compound B and benzyl chloroformate is (0.8 ~ 1): (1 ~ 5).
Preferably, the solvent in the S4 is in acetonitrile, toluene, acetone, methylene chloride, 1,2- dioxane and water It is any or a combination thereof；Alkali in the S4 is potassium carbonate, sodium carbonate, triethylamine, diisopropyl ethyl amine, DBU, hydroxide Potassium, lithium hydroxide, sodium methoxide, in sodium ethoxide any one or combinations thereof；The throwing amount equivalents ratio of the compound C and alkali is (0.8 ~ 1): (1 ~ 5).
Preferably, the solvent in the S5 is toluene, acetone, methylene chloride, 1,2- dioxane, methanol, ethyl alcohol, isopropyl Any one of alcohol, benzyl alcohol and water or a combination thereof；Alkali in the S5 is triethylamine, diisopropyl ethyl amine, two different Propylamine, DBU, potassium hydroxide, in lithium hydroxide any one or combinations thereof；The throwing amount of compound D and alkali in the S5 are worked as Amount ratio is 1:(1 ~ 10).
Preferably, the throwing amount equivalents ratio of the compound D and catalyst is 1:(0.001 ~ 0.3).
Preferably, the catalyst is S-segphos Ru (OAc) 2.
By using above-mentioned technical proposal, so that reaction rate improves, (3R, 4S) -1- benzyloxy suitable for industrialization is obtained Carbonyl -4- N-ethyl pyrrole N -3- carboxylic acid.
In conclusion the invention has the following advantages:
(1) a kind of synthetic method of (3R, 4S) -1- substitution -4- N-ethyl pyrrole N -3- carboxylic acid suitable for industrialization of the invention is logical The reaction of five steps is crossed, operating method is simple, has obtained purity and all higher (3R, the 4S) -1- benzyloxycarbonyl group -4- ethyl pyrrole of yield - 3- carboxylic acid is coughed up, solves the problems, such as that quality in the prior art and yield are difficult to control, has saved the reaction time, reduced system Standby cost；
(2) the synthetic method behaviour of a kind of (3R, 4S) -1- substitution -4- N-ethyl pyrrole N -3- carboxylic acid suitable for industrialization of the invention It is easily controllable to make condition, is split without multiple, reduces processing step.
Specific embodiment
The invention will be further described below.Following embodiment is only used for clearly illustrating technical side of the invention Case, and not intended to limit the protection scope of the present invention.
A kind of synthetic method of (3R, 4S) -1- benzyloxycarbonyl group -4- N-ethyl pyrrole N -3- carboxylic acid suitable for industrialization, it is special Sign is, comprising the following steps:
S1, using valerylene acid esters and N- methoxy-N- (trimethylsilylmethyl) benzyl amine as starting material, in a solvent Intermediate condensation midbody product compound A, the structural formula of the compound A are prepared through being condensed ring closure reaction under acid catalysis Are as follows:
；
Compound A is added in solvent by S2, stirring, and after 0 ~ 5 DEG C of addition ethyl chloroformate, 1 ~ 2h is reacted at 20 ~ 25 DEG C Afterwards, alcohols solvent is added, the reaction was continued at 40 ~ 90 DEG C, obtains midbody product compound B, the structural formula of the compound B Are as follows:
；
S3, under the conditions of alkali, compound B prepares N protection intermediates through acylation reaction with protecting group reagent in a solvent and produces Compounds C, the structural formula of the compound C are as follows:
；
S4, under alkaline condition, compound C prepares midbody product compound D, describedization through ester hydrolysis reaction in a solvent Close the structural formula of object D are as follows:
；
Compound D is crystallized to obtain intermediate sterling through processing by S5, in a solvent, under the conditions of catalyst is existing, is passed through with hydrogen Asymmetric reduction reaction obtains (3R, 4S) -1- benzyloxycarbonyl group -4- N-ethyl pyrrole N -3- carboxylic acid, structural formula are as follows:
。
The synthetic route of (3R, 4S) -1- benzyloxycarbonyl group -4- N-ethyl pyrrole N -3- carboxylic acid are as follows:
By using above-mentioned technical proposal, five steps react (3R, the 4S) -1- benzyloxycarbonyl group -4- N-ethyl pyrrole N -3- carboxylic being prepared Acid, and easily-controlled reaction conditions.
Embodiment 1
50.0g pentyne acetoacetic ester (1.0eq, 0.396mol) is added in reaction flask S1, addition 141.15g (1.5eq, Acetonitrile 750mL, room temperature are added into above-mentioned reaction flask for 0.594mol) N- (methoxyl methyl)-N- (trimethyl silicane methyl) benzylamine Under, it is added dropwise to concentrated hydrochloric acid/aqueous solution 3.8g/20ml(0.1eq, 0.0396mol), about 30min is added dropwise.Holding room temperature 20 ~ 25 DEG C of reaction 16h.
Post-processing: after reaction, concentration removal acetonitrile is added ethyl acetate 700ml, uses saturated aqueous solution of sodium bicarbonate It washes twice (250mL × 2), then washed once (250mL × 1) with sodium-chloride water solution；Organic phase is evaporated under reduced pressure to no fraction Generate (40 ~ 50 DEG C, -0.1Mpa), directly with enter next step.
Reaction equation are as follows:
。
S2, by previous step crude Compound A(1.0eq, 0.396mol), 1500mL methylene chloride puts into reaction flask, stirs It mixes to dissolved clarification；Chloro-carbonic acid 2- chloroethene ester 169.84g(3.0eq, 1.188mol are added at 0 DEG C), it is kept stirring uniformly.In being warming up to It warm 20-25 DEG C, is stirred to react 1-2 hours；TLC is detected without raw material point；
(20-25 DEG C) 100mL methanol is added into product under room temperature；40 DEG C are heated to react 6 hours；TLC is detected without raw material Point；
Post-processing: (40-50 DEG C, -0.1Mpa) of evaporated under reduced pressure obtains crude product, directly carries out in next step.
Reaction equation are as follows:
。
S3 in the reaction flask of previous step crude compound B (1.0eq, 0.396mol), is added 500mL acetone and is kept stirring, Nitrogen protection.Ice-water bath is cooled to 0 DEG C, is added triethylamine 119.98g (3.0eq, 1.188mol), keeps that CbzCl is added at 0 DEG C (101.33g, 1.5eq, 0.594mol)/acetone (400ml) solution, about 1h are added dropwise, then are warming up to 25 DEG C of interior temperature reactions 1h。
Post-processing: being added tap water 400ml quenching reaction, and 40 ~ 45 DEG C of reduced pressures remove solvent acetone, acetic acid second is added Ester 800ml, layering remove water phase, and organic phase uses tap water 400ml extraction primary again, and organic phase evaporated under reduced pressure to no fraction produces Raw, crude product directly carries out in next step.
Reaction equation are as follows:
。
In the reaction flask of previous step crude reaction compound C, 300mL methanol is added in S4, and being kept stirring makes to dissolve, cooling To about 0-5 DEG C of interior temperature, it is added dropwise in the 1N lithium hydroxide aqueous solution investment reaction flask of 20ml, stirring keeps room temperature reaction about 4h；
TLC detects fully reacting；
Post-processing: removing most of methanol under reduced pressure, and 200mL ethyl acetate is added and 100ml water stirs 10 minutes, is layered, removes Ethyl acetate phase；500mL ethyl acetate is added under ice bath in water phase, adjusts water phase pH to 4 with concentrated hydrochloric acid；Layering, water phase are used again The extraction of 200mL ethyl acetate is primary, merges organic phase, and organic phase is concentrated under reduced pressure into no fraction and generates；100ml methanol, ice is added Bath lower stirring 3 hours, there is solid precipitation；Filtering, collects solid, and 45 DEG C of solid decompression dryings obtain product 43g, four step total recoverys 39.4%。
Reaction equation are as follows:
。
Previous step product 42.75g(1.0eq, 0.156mol) is added in hydrogen reaction kettle S5, addition 1.4g ( 0.025eq, 0.004mol) (solvent methanol 600ml is added in S-segphos Ru (OAc) 2 to catalyst, and diisopropylamine is added 47.27g(3.0eq, 0.468mol), it is kept stirring uniformly, nitrogen is replaced 3 times, then logical hydrogen is replaced 3 times, and Hydrogen Vapor Pressure is increased To 2.0MPa, keep reacting 6h at 30 DEG C of temperature；
Post-processing: after fully reacting, displacement nitrogen displacement removal hydrogen, diatomite is filtered, and filter cake is washed with methanol (100ml*3) Three times；Mother liquor evaporated under reduced pressure obtains 39g colourless oil liquid.
Reaction equation are as follows:
。
The above is only a preferred embodiment of the present invention, protection scope of the present invention is not limited merely to above-mentioned implementation Example, all technical solutions belonged under thinking of the present invention all belong to the scope of protection of the present invention.It should be pointed out that for the art Those of ordinary skill for, several improvements and modifications without departing from the principles of the present invention, these improvements and modifications It should be regarded as protection scope of the present invention.

Claims (10)

1. a kind of synthetic method of (3R, 4S) -1- benzyloxycarbonyl group -4- N-ethyl pyrrole N -3- carboxylic acid suitable for industrialization, feature It is, comprising the following steps:
S1, using valerylene acid esters and N- methoxy-N- (trimethylsilylmethyl) benzyl amine as starting material, in a solvent Intermediate condensation midbody product compound A, the structural formula of the compound A are prepared through being condensed ring closure reaction under acid catalysis Are as follows:
；
Compound A is added in solvent by S2, stirring, and after 0 ~ 5 DEG C of addition ethyl chloroformate, 1 ~ 2h is reacted at 20 ~ 25 DEG C Afterwards, alcohols solvent is added, the reaction was continued at 40 ~ 90 DEG C, obtains midbody product compound B, the structural formula of the compound B Are as follows:
；
S3, under the conditions of alkali, compound B prepares N protection intermediates through acylation reaction with benzyl chloroformate in a solvent and produces Compounds C, the structural formula of the compound C are as follows:
；
S4, under alkaline condition, compound C prepares midbody product compound D, describedization through ester hydrolysis reaction in a solvent Close the structural formula of object D are as follows:
；
Compound D is crystallized to obtain intermediate sterling through processing by S5, in a solvent, under the conditions of catalyst is existing, is passed through with hydrogen Asymmetric reduction reaction obtains (3R, 4S) -1- benzyloxycarbonyl group -4- N-ethyl pyrrole N -3- carboxylic acid, structural formula are as follows:
。
2. a kind of (3R, 4S) -1- benzyloxycarbonyl group -4- N-ethyl pyrrole N -3- carboxylic suitable for industrialization according to claim 1 The synthetic method of acid, characterized in that the valerylene acid esters in the S1 is valerylene acid methyl esters, valerylene acetoacetic ester or valerylene One of tert-butyl acrylate；
The R1For methyl, ethyl or tert-butyl；
Solvent in the S1 is ethyl acetate, in acetonitrile, toluene, acetone, methylene chloride, chloroform, 1,2- dichloroethanes It is any or a combination thereof；
Acid in the S1 be any one of acetic acid, methane sulfonic acid, hydrochloric acid, sulfuric acid, trifluoroacetic acid, p-methyl benzenesulfonic acid or A combination thereof.
3. a kind of (3R, 4S) -1- benzyloxycarbonyl group -4- N-ethyl pyrrole N-suitable for industrialization according to claim 1 or 2 The synthetic method of 3- carboxylic acid, characterized in that valerylene acid esters and N- methoxy-N- (trimethylsilylmethyl) in the S1 Benzyl amine equivalents ratio is 0.8:1 ~ 1:2.
4. a kind of (3R, 4S) -1- benzyloxycarbonyl group -4- N-ethyl pyrrole N -3- carboxylic suitable for industrialization according to claim 1 The synthetic method of acid, characterized in that the reaction temperature in the S1 is -5 ~ 50 DEG C.
5. a kind of (3R, 4S) -1- benzyloxycarbonyl group -4- N-ethyl pyrrole N -3- carboxylic suitable for industrialization according to claim 1 The synthetic method of acid, characterized in that solvent is ethyl acetate, acetonitrile, toluene, acetone, methylene chloride, three chloromethanes in the S2 Any one of alkane, 1,2- dichloroethanes or a combination thereof；The equivalents ratio of compound A and ethyl chloroformate is in the S2 (0.8 ~ 1): (1 ~ 5)；
Alcohols solvent is one of methanol, ethyl alcohol, isopropanol or combinations thereof in the S2.
6. a kind of (3R, 4S) -1- benzyloxycarbonyl group -4- N-ethyl pyrrole N -3- carboxylic suitable for industrialization according to claim 1 The synthetic method of acid, characterized in that the solvent in the S3 is ethyl acetate, acetonitrile, toluene, acetone, methylene chloride and water Any one of or a combination thereof；
Alkali in the S3 is any one of triethylamine, DBU, sodium carbonate, potassium carbonate, potassium hydroxide, saleratus or its group It closes；
The equivalents ratio that feeds intake of the compound B and benzyl chloroformate is (0.8 ~ 1): (1 ~ 5).
7. a kind of (3R, 4S) -1- benzyloxycarbonyl group -4- N-ethyl pyrrole N -3- carboxylic suitable for industrialization according to claim 1 The synthetic method of acid, characterized in that solvent in the S4 be acetonitrile, toluene, acetone, methylene chloride, 1,2- dioxane with And any one of water or a combination thereof；
Alkali in the S4 be potassium carbonate, sodium carbonate, triethylamine, diisopropyl ethyl amine, DBU, potassium hydroxide, lithium hydroxide, In sodium methoxide, sodium ethoxide any one or combinations thereof；
The throwing amount equivalents ratio of the compound C and alkali is (0.8 ~ 1): (1 ~ 5).
8. a kind of (3R, 4S) -1- benzyloxycarbonyl group -4- N-ethyl pyrrole N -3- carboxylic suitable for industrialization according to claim 1 The synthetic method of acid, characterized in that the solvent in the S5 is toluene, acetone, methylene chloride, 1,2- dioxane, methanol, second Any one of alcohol, isopropanol, benzyl alcohol and water or a combination thereof；
Alkali in the S5 is triethylamine, diisopropyl ethyl amine, diisopropylamine, DBU, potassium hydroxide, appointing in lithium hydroxide It anticipates one kind or combinations thereof；
The throwing amount equivalents ratio of compound D and alkali in the S5 are 1:(1 ~ 10).
9. a kind of (3R, 4S) -1- benzyloxycarbonyl group -4- N-ethyl pyrrole N -3- carboxylic suitable for industrialization according to claim 8 The synthetic method of acid, characterized in that the throwing amount equivalents ratio of the compound D and catalyst is 1:(0.001 ~ 0.3).
10. a kind of (3R, 4S) -1- benzyloxycarbonyl group -4- N-ethyl pyrrole N-suitable for industrialization according to claim 8 or claim 9 The synthetic method of 3- carboxylic acid, characterized in that the catalyst is S-segphos Ru (OAc) 2.
CN201910498948.7A 2019-06-11 2019-06-11 A kind of synthetic method of (3R, 4S) -1- benzyloxycarbonyl group -4- N-ethyl pyrrole N -3- carboxylic acid suitable for industrialization Pending CN110183367A (en)

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CN111454189A (en) * 2020-05-12 2020-07-28 苏州旺山旺水生物医药有限公司 Synthetic method of sepiatinib intermediate
CN112538010A (en) * 2019-09-20 2021-03-23 凯特立斯（深圳）科技有限公司 Preparation method of key intermediate for synthesizing artemisinin compound

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CN109705011A (en) * 2019-01-18 2019-05-03 浙江师范大学 A kind of crow pa replaces the synthetic method and intermediate of Buddhist nun's intermediate

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CN109705011A (en) * 2019-01-18 2019-05-03 浙江师范大学 A kind of crow pa replaces the synthetic method and intermediate of Buddhist nun's intermediate

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CN112538010A (en) * 2019-09-20 2021-03-23 凯特立斯（深圳）科技有限公司 Preparation method of key intermediate for synthesizing artemisinin compound
CN112538010B (en) * 2019-09-20 2023-08-11 凯特立斯（深圳）科技有限公司 Preparation method of artemisinin compound synthesized key intermediate
CN111454189A (en) * 2020-05-12 2020-07-28 苏州旺山旺水生物医药有限公司 Synthetic method of sepiatinib intermediate
CN111454189B (en) * 2020-05-12 2021-11-23 苏州旺山旺水生物医药有限公司 Synthetic method of sepiatinib intermediate

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