CN110183368A - The synthetic method of (3R, 4S) -1- fluorenylmethyloxycarbonyl -4- N-ethyl pyrrole N -3- carboxylic acid suitable for industrialization - Google Patents
The synthetic method of (3R, 4S) -1- fluorenylmethyloxycarbonyl -4- N-ethyl pyrrole N -3- carboxylic acid suitable for industrialization Download PDFInfo
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- CN110183368A CN110183368A CN201910498953.8A CN201910498953A CN110183368A CN 110183368 A CN110183368 A CN 110183368A CN 201910498953 A CN201910498953 A CN 201910498953A CN 110183368 A CN110183368 A CN 110183368A
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- fluorenylmethyloxycarbonyl
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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
Abstract
The invention discloses a kind of (3R suitable for industrialization, 4S) the synthetic method of -1- fluorenylmethyloxycarbonyl -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 to prepare N protection midbody products through acylation reaction with fluorenes methoxy dicarbonyl chloride; with hydrogen after asymmetric reduction reaction; through ester hydrolysis reaction; obtain (3R, 4S) -1- fluorenylmethyloxycarbonyl -4- N-ethyl pyrrole N -3- carboxylic acid.The present invention is reacted by five steps, purity and all higher (3R, the 4S) -1- fluorenylmethyloxycarbonyl -4- N-ethyl pyrrole N -3- carboxylic acid of yield have been obtained, has solved the problems, such as that quality in the prior art and yield are difficult to control, the reaction time has been saved, preparation cost is reduced.
Description
Technical field
The present invention relates to a kind of (3R, 4S) -1- fluorenylmethyloxycarbonyl -4- N-ethyl pyrrole N -3- carboxylic acids suitable for industrialization
Synthetic method belongs to chipal compounds synthesis technical field.
Background technique
Black pa is a kind of oral JAK1 inhibitor for Buddhist nun, for treating the diseases such as rheumatoid arthritis, psoriatic arthritis.
Jak kinase is a kind of nonreceptor tyrosine kinase family, it has been found that four members, i.e. JAK1, JAK2, JAK3 and TYK1.JAK
Substrate be STAT, i.e. signal transducer and transcription activator.After JAK phosphorylation dimerization is occurred for STAT, then passes through nuclear membrane
The expression of related gene is adjusted in into core, which is known as JAK-STAT approach, therefore JAK is in immune-mediated disease
It plays a significant role in pathophysiological process, can be used for treating some autoimmune diseases and such as treat atopic dermatitis, wind
Wet arthritis, psoriasis, ulcerative colitis etc..
Black pa is complicated for the synthesis path of Buddhist nun, black pa is prepared again for Buddhist nun's production generally by being formed behind drug centre
Product are used for clinical test and treatment.
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- fluorenylmethyloxycarbonyl -4- N-ethyl pyrrole N -3- carboxylic acid.The major defect of the technique
It for synthesising racemation type precursor, then splits again, theoretical highest yield 50%, net yield is about that 14.75%(is respectively walked disclosure by document
Yield data combination resolution yield 100% calculates).Meanwhile product boiling point is extremely low after the reduction of the technique first step, at 25 DEG C of temperature
Decompression is i.e. readily volatilized, largely effects on process recovery ratio, is unfavorable for industrialization production, while intermediate is purple after third step deprotection
Outer 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.
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- fluorenylmethyloxycarbonyl -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- fluorenylmethyloxycarbonyl -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 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 fluorenes methoxy dicarbonyl chloride in a solvent
Product Compound C, the structural formula of the compound C are as follows:
；
S4 in a solvent by compound C under the conditions of catalyst is existing, with hydrogen through asymmetric reduction reaction, obtains intermediate
Compound D, structural formula are as follows:
；
S5, under alkaline condition, compound D prepares (3R, 4S) -1- fluorenylmethyloxycarbonyl -4- through ester hydrolysis reaction in a solvent
N-ethyl pyrrole N -3- carboxylic acid, structural formula are as follows:
。
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 compound B and feed intake equivalents ratio be (0.8 ~ 1): (1 ~ 5).
Preferably, the solvent in the S4 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 S4 is triethylamine, diisopropyl ethyl amine, two different
Propylamine, DBU, potassium hydroxide, in lithium hydroxide any one or combinations thereof；
Preferably, the solvent in the S5 is any in acetonitrile, toluene, acetone, methylene chloride, 1,2- dioxane and water
Kind or a combination thereof；Alkali in the S5 be potassium carbonate, sodium carbonate, triethylamine, diisopropyl ethyl amine, DBU, potassium hydroxide,
Lithium hydroxide, sodium methoxide, in sodium ethoxide any one or combinations thereof.
Preferably, the catalyst is S-segphos Ru (OAc) 2.
In conclusion the invention has the following advantages:
(1) synthesis of a kind of (3R, 4S) -1- fluorenylmethyloxycarbonyl -4- N-ethyl pyrrole N -3- carboxylic acid suitable for industrialization of the invention
Method is reacted by five steps, and operating method is simple, has obtained purity and all higher (3R, the 4S) -1- fluorenylmethyloxycarbonyl -4- of yield
N-ethyl pyrrole N -3- carboxylic acid solves the problems, such as that quality in the prior art and yield are difficult to control, has saved the reaction time, dropped
Low preparation cost；
(2) adjustment of the invention by processing route, preparation first pass through catalytic hydrogenation and hydrolyze to obtain (3R, 4S) -1- fluorenes methoxy again
The purity and yield of carbonyl -4- N-ethyl pyrrole N -3- carboxylic acid are higher, and post-process simple.
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- fluorenylmethyloxycarbonyl -4- N-ethyl pyrrole N -3- carboxylic acid suitable for industrialization,
It is characterized in, comprising the following steps:
S1, using valerylene acid esters and N- methoxy-N- (trimethylsilylmethyl) benzyl amine as starting material, in a solvent
Intermediate condensation 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 fluorenes methoxy dicarbonyl chloride in a solvent
Product Compound C, the structural formula of the compound C are as follows:
；
S4 in a solvent by compound C under the conditions of catalyst is existing, with hydrogen through asymmetric reduction reaction, obtains intermediate
Compound D, structural formula are as follows:
；
S5, under alkaline condition, compound D prepares (3R, 4S) -1- fluorenylmethyloxycarbonyl -4- through ester hydrolysis reaction in a solvent
N-ethyl pyrrole N -3- carboxylic acid, structural formula are as follows:
。
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 is put into reaction flask, and stirring is extremely
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.It is warming up to interior temperature
It 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 FmocCl is added at 0 DEG C
(153.66g, 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, ethyl acetate is added
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 generates,
Crude product directly carries out in next step.
Reaction equation are as follows:
S4 will be added in hydrogen reaction kettle after previous step product (1.0eq, 0.156mol) drying, addition 1.4g (0.025eq,
0.004mol) (solvent methanol 600ml is added in S-segphos Ru (OAc) 2 to catalyst, and diisopropylamine 47.27g is added
(3.0eq, 0.468mol) is kept stirring uniformly, and nitrogen is replaced 3 times, then logical hydrogen is replaced 3 times, increases Hydrogen Vapor Pressure extremely
2.0MPa keeps 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；
；
S5, previous step crude reaction compound D are added in reaction flask, and 300mL methanol is added, 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 4h,
Obtain target product；
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；Solid, 45 DEG C of solid decompression dryings are collected in filtering.
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 (9)
1. a kind of synthetic method of (3R, 4S) -1- fluorenylmethyloxycarbonyl -4- N-ethyl pyrrole N -3- carboxylic acid suitable for industrialization, 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 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 fluorenes methoxy dicarbonyl chloride in a solvent
Product Compound C, the structural formula of the compound C are as follows:
；
S4 in a solvent by compound C under the conditions of catalyst is existing, with hydrogen through asymmetric reduction reaction, obtains intermediate
Compound D, structural formula are as follows:
；
S5, under alkaline condition, compound D prepares (3R, 4S) -1- fluorenylmethyloxycarbonyl -4- through ester hydrolysis reaction in a solvent
N-ethyl pyrrole N -3- carboxylic acid, structural formula are as follows:
。
2. a kind of (3R, 4S) -1- fluorenylmethyloxycarbonyl -4- N-ethyl pyrrole N -3- suitable for industrialization according to claim 1
The synthetic method of carboxylic acid, characterized in that the valerylene acid esters in the S1 is valerylene acid methyl esters, valerylene acetoacetic ester or 2- penta
One of acetylenic acid tert-butyl ester；
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- fluorenylmethyloxycarbonyl -4- ethyl pyrrole suitable for industrialization according to claim 1 or 2
Cough up the synthetic method of -3- carboxylic acid, characterized in that valerylene acid esters and N- methoxy-N- (trimethyl silane first in the S1
Base) benzyl amine equivalents ratio be 0.8:1 ~ 1:2.
4. a kind of (3R, 4S) -1- fluorenylmethyloxycarbonyl -4- N-ethyl pyrrole N -3- suitable for industrialization according to claim 1
The synthetic method of carboxylic acid, characterized in that the reaction temperature in the S1 is -5 ~ 50 DEG C.
5. a kind of (3R, 4S) -1- fluorenylmethyloxycarbonyl -4- N-ethyl pyrrole N -3- suitable for industrialization according to claim 1
The synthetic method of carboxylic 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- fluorenylmethyloxycarbonyl -4- N-ethyl pyrrole N -3- suitable for industrialization according to claim 1
The synthetic method of carboxylic acid, characterized in that solvent in the S3 be ethyl acetate, acetonitrile, toluene, acetone, methylene chloride and
Any one of water 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 compound B and feed intake equivalents ratio be (0.8 ~ 1): (1 ~ 5).
7. a kind of (3R, 4S) -1- fluorenylmethyloxycarbonyl -4- N-ethyl pyrrole N -3- suitable for industrialization according to claim 1
The synthetic method of carboxylic acid, characterized in that solvent in the S4 be toluene, acetone, methylene chloride, 1,2- dioxane, methanol,
Any one of ethyl alcohol, isopropanol, benzyl alcohol and water or a combination thereof；
Alkali in the S4 is triethylamine, diisopropyl ethyl amine, diisopropylamine, DBU, potassium hydroxide, appointing in lithium hydroxide
It anticipates one kind or combinations thereof.
8. a kind of (3R, 4S) -1- fluorenylmethyloxycarbonyl -4- N-ethyl pyrrole N -3- suitable for industrialization according to claim 1
The synthetic method of carboxylic acid, characterized in that the solvent in the S5 is acetonitrile, toluene, acetone, methylene chloride, 1,2- dioxane
And any one of water or a combination thereof；
Alkali in the S5 be potassium carbonate, sodium carbonate, triethylamine, diisopropyl ethyl amine, DBU, potassium hydroxide, lithium hydroxide,
In sodium methoxide, sodium ethoxide any one or combinations thereof.
9. a kind of (3R, 4S) -1- fluorenylmethyloxycarbonyl -4- N-ethyl pyrrole N -3- suitable for industrialization according to claim 1
The synthetic method of carboxylic acid, characterized in that the catalyst is S-segphos Ru (OAc) 2.
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| CN111072543A (en) * | 2019-11-13 | 2020-04-28 | 北京海美桐医药科技有限公司 | Preparation method and application of (3R,4S) -4-ethylpyrrolidine-3-carboxylic acid compound |
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| Publication number | Priority date | Publication date | Assignee | Title |
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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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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111072543A (en) * | 2019-11-13 | 2020-04-28 | 北京海美桐医药科技有限公司 | Preparation method and application of (3R,4S) -4-ethylpyrrolidine-3-carboxylic acid compound |
| CN111072543B (en) * | 2019-11-13 | 2021-06-04 | 北京海美桐医药科技有限公司 | Preparation method and application of (3R,4S) -4-ethylpyrrolidine-3-carboxylic acid compound |
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Application publication date: 20190830 |