CN107176955A - A kind of Ba Rui replaces the preparation method of Buddhist nun - Google Patents
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Abstract
The invention discloses the preparation method that a kind of Ba Rui replaces Buddhist nun, with 4 chlorine 7H pyrrolo-es [2,3 d] pyrimidines (II) for raw material, it is substituted reaction in the presence of a base with benzene sulfonyl chloride and intermediate III is made；Then in the presence of palladium catalytic system and alkali, intermediate V is made through Suzuki coupling reactions with 4 pyrazoles pinacol borates in intermediate III；Then intermediate VII is made through Michael addition reaction in the presence of a catalyst in intermediate V and the t-butyl formate of 3 (cyanomethylene) azetidine 1；Then intermediate VIII is made in intermediate VII removing Boc protections under hydrochloric acid effect；Then in the presence of a base, intermediate compound I X is made through sulfonamide reaction in organic solvent with ethyl sulfonic chloride in intermediate VIII；Last intermediate compound I X removing benzenesulfonyl protections under the effect of one of Methanaminium, N,N,N-trimethyl-, fluoride or tetrabutyl ammonium fluoride or the trihydrate of the two, produce Ba Rui for Buddhist nun (I).Compared with prior art, the method for the invention has the advantages that raw material is easy to get, with low cost, product yield is high and is easy to industrialized production.
Description
Technical field
The present invention relates to pharmaceutical synthesis field, and in particular to a kind of Pyrrolopyrimidine JAK inhibitor medicaments Ba Rui replaces Buddhist nun
Preparation Method And Their Intermediate compound.
Background technology
Ba Rui is by gift is total to come pharmacy collaboration partner Incyte companies for Buddhist nun (Baricitinib, Olumiant, 1)
With a kind of selective JAK1 and JAK2 inhibitor of exploitation, the cell of a variety of inflammatory cytokines such as IL-6 and IL-23 can be suppressed
Interior signal transduction, chemical entitled 1- (ethylsulfonyl) -3- [4- (7H- pyrrolo-es [2,3-d] pyrimidine-4-yl) -1H- pyrazoles -1-
Base] -3- azetidine acetonitriles, shown in its structural formula such as formula (I).The product were ratified in being used to treat extremely in 2017 by European Union
Severe rheumatoid arthritis, the adult that current rheumatoid arthritis agents are not reacted or do not tolerated, it can conduct
Single medicine is used, and can be also used together with widely used methotrexate (MTX).
Prior art is disclosed mainly to be had for preparing Ba Rui for the method for Buddhist nun：
(1) Incyte companies report the synthetic route that a Ba Rui replaces Buddhist nun in patent WO2009114512A1, as follows
It is shown：
Meanwhile, the patent, which is also disclosed, uses N- oxy acid methyl neopentyls chlorine (POM-Cl) instead to 4- chlorine pyrrolo- [2,3-d]
The similar scheme that N on pyrimidine (2) is protected.
However, above-mentioned reaction scheme is tediously long, NaH has been used in the N protection reactions of 4- chlorine pyrrolo- [2,3-d] pyrimidine (2), is grasped
Make complicated, and subsequently need to can be just deprotected through two-step reaction during SEM protections, more bother, the Suzuki of intermediate 3 and 4
Coupling reaction need to could be carried out after pyrazoles NH is protected, and thus be also add follow-up deprotection operation, caused gross production rate inclined
It is low.In addition, SEM-Cl or POM-Cl are expensive, production cost is caused to increase.
(2) CN105294699A also discloses that a kind of Ba Rui replaces the synthesis technique of Buddhist nun：
The N protection groups of N protection groups and azetidine on technique adjustment pyrrolopyrimidine ring are Boc, so as to through a step
Deprotection reaction and remove, but final step second sulfonylation need to carry out prolonged low-temperature operation, otherwise may cause
NH on pyrrolopyrimidine ring is influenceed yield by sulfonylation.
(3) CN105541891A also discloses that a kind of Ba Rui replaces the synthesis technique of Buddhist nun：
The azetidine raw material 10 that the technique is directly replaced with ethylsulfonyl carries out Michael addition reactions, so that
Amido protecting and follow-up deprotection need not be carried out by obtaining the intermediate 11 in Suzuki coupling reactions, shorten reactions steps,
But the separation of borate intermediate 11 uses column chromatography, and borate may be adsorbed for boric acid because of partial hydrolysis, causes
Certain product loss.
The content of the invention
For problems of the prior art, it is an object of the invention to provide the preparation method that a kind of Ba Rui replaces Buddhist nun, sheet
The there is provided process route raw material of invention is easy to get, concise in technology, economic and environment-friendly and suitable industrialized production.
Ba Rui disclosed by the invention replaces the preparation method of Buddhist nun, comprises the following steps：
(1) with chloro- 7H- pyrrolo-es [2, the 3-d] pyrimidines (II) of 4- for raw material, it is substituted in the presence of a base with benzene sulfonyl chloride anti-
Intermediate 4- chloro- 7- (benzenesulfonyl) -7H- pyrrolo-es [2,3-d] pyrimidine (III) should be made；
(2) in the presence of palladium catalytic system and alkali, intermediate III is coupled anti-with 4- pyrazoles pinacol borate through Suzuki
Intermediate 7- (benzenesulfonyl) -4- (1H- pyrazoles -4- bases) -7H- pyrrolo-es [2,3-d] pyrimidine (V) should be made；
(3) intermediate V and 3- (cyanomethylene) azetidine -1- t-butyl formates are in the presence of a catalyst through mikey
Intermediate 3- (cyano methyl) -3- (4- (7- benzenesulfonyls) -7H- pyrrolo-es [2,3-d] pyrimidine -4- are made for addition reaction in you
Base) -1H pyrazol-1-yls) azetidine -1- t-butyl formates (VII)；
(4) intermediate 3- (cyanomethylene) -3- ((7- benzene is made in intermediate VII removing Boc protections under hydrochloric acid effect
Sulfonyl) -7H- pyrrolo-es [2,3-d] pyrimidine-4-yl) -1H- pyrazol-1-yls) azetidine hydrochloride (VIII)；
(5) in the presence of alkali, intermediate is made through sulfonamide reaction in organic solvent with ethyl sulfonic chloride in intermediate VIII
IX；
(6) intermediate compound I X is removed under the effect of one of Methanaminium, N,N,N-trimethyl-, fluoride or tetrabutyl ammonium fluoride or the trihydrate of the two
Benzenesulfonyl is protected, and produces target product Ba Rui for Buddhist nun (I).
Reaction equation is as follows：
In step (1), the mol ratio of chloro- 7H- pyrrolo-es [2, the 3-d] pyrimidines (II) of 4- and benzene sulfonyl chloride is 1：
(1.1-1.4)；The alkali may be selected from potassium tert-butoxide, sodium tert-butoxide, NaH, potassium carbonate, sodium carbonate；The chloro- 7H- pyrrolo-es of 4-
The consumption mol ratio of [2,3-d] pyrimidine (II) and alkali is 1：(1.1-1.3)；Reaction dissolvent is in tetrahydrofuran, acetonitrile, DMF
One or more；The reaction temperature is 0 DEG C-room temperature, and the reaction time is 3-5h.
In step (2), the mol ratio of the intermediate III and 4- pyrazoles pinacol borate (IV) is 1：(1.1-1.3)；
The palladium catalytic system is selected from Pd (PPh3)4、Pd(PPh3)4Cl2、Pd(PPh3)2Cl2、Pd(OAc)2/PPh3；The alkali is selected from alkali
Metal carbonate or alkali metal hydrogencarbonate, preferably potassium carbonate；The intermediate III and palladium catalyst, the mol ratio of alkali are 1：
(0.01-0.03)：(2-4).
In step (3), intermediate V and 3- (cyanomethylene) azetidine -1- t-butyl formate (VI's) rubs
You are than being 1:(1-1.4)；The catalyst of the Michael addition reaction is selected from DBU, alkali metal hydroxide, urea or thiocarbamide；
One or more of the reaction dissolvent in DMF, acetonitrile, isopropanol；The mol ratio of the intermediate V and catalyst are 1：
(0.03-0.06)。
In step (4), the mol ratio of the intermediate VII and hydrochloric acid are 1:(2.2-2.6)；The hydrochloric acid can use dense salt
The aqueous hydrochloric acid solution of acid or 15%-35%；One kind in methanol, absolute ethyl alcohol, isopropanol, tetrahydrofuran of reaction dissolvent or
It is several, preferred absolute ethyl alcohol.
In step (5), the alkali is tertiary amine, preferably DIPEA or triethylamine, more preferably N, N- diisopropyls
Base ethamine；The mol ratio of the intermediate VIII and ethyl sulfonic chloride, alkali is 1:(1-1.3):(2.1-2.4)；Reaction dissolvent is selected from
One or more in dichloromethane, acetonitrile, tetrahydrofuran；The reaction temperature is 0 DEG C-room temperature；Reaction time 10-18h.
In step (6), the intermediate compound I X and Methanaminium, N,N,N-trimethyl-, fluoride or tetrabutyl ammonium fluoride or the trihydrate of the two it
One mol ratio is 1:(2.5-4)；Reaction dissolvent is selected from tetrahydrofuran or 2- methyltetrahydrofurans；Reaction temperature be 60 DEG C-it is molten
Agent reflux temperature；Reaction time 10-18h.
Compared with prior art, Ba Rui of the present invention for Buddhist nun (I) preparation method there is raw material to be easy to get, cost it is low
Honest and clean, technique is simple, mild condition, simple operation, product yield is high and is easy to the advantage of industrialized production.
Embodiment
Below in conjunction with specific embodiment, the present invention is further elaborated.
Embodiment 1
The preparation of 4- chloro- 7- (benzenesulfonyl) -7H- pyrrolo-es [2,3-d] pyrimidines (III)
Chloro- 7H- pyrrolo-es [2, the 3-d] pyrimidines (II, 15.00g, 0.098mol) of 4- are dissolved in 400mL THF, Ran Houjia
Enter potassium tert-butoxide (13.70g, 0.122mol), 20min is stirred at room temperature in reactant mixture, when the reaction is exothermic, using ice-water bath
Supplement heat rejecter, benzene sulfonyl chloride (15.6mL, 0.122mol) is added dropwise into mixed liquor, and drop finishes stirring 3h.Stop reaction, decompression is removed
Reaction solution is slowly poured into 600mL mixture of ice and water after partial solvent and stirs 30min, there are a large amount of solids to wash out, after filtering
It is dried in vacuo to obtain white solid i.e. 4- chloro- 7- (phenyl sulfonyl) -7H- pyrrolo-es [2,3-d] pyrimidine (25.64g, yield
89.1%).MS m/z 294[M+1]+；1H-NMR(400M,CDCl3)δ：8.78 (s, 1H), 8.22 (d, 2H), 7.65 (t, 1H),
7.57-7.55 (t, 1H), 6.73-6.72 (d, 1H) ppm.
Embodiment 2
The preparation of 7- (benzenesulfonyl) -4- (1H- pyrazoles -4- bases) -7H- pyrrolo-es [2,3-d] pyrimidine (V)
At room temperature, by 4- chloro- 7- (phenyl sulfonyl) -7H- pyrrolo-es [2,3-d] pyrimidine (III, 10.00g,
0.034mol), water (50mL) and potassium carbonate (14.12g, 0.102mol) are added in 500mL reaction bulbs, then add 4- pyrazoles boron
Sour pinacol ester (IV, 7.93g, 0.041mol), DMF (100mL) and Pd (PPh3)4(0.59g, 0.511mmol).Reaction is mixed
Compound is heated to 80-85 DEG C, then insulated and stirred 4 hours.Monitored and reacted by TLC, after reaction completely, added into reaction bulb
500mL mixture of ice and water, stirs 20min, separates out solid, dry crude product after filtering, and then crude product is added using 50mL isopropanols
Heat of solution, is filtered to remove insoluble matter while hot, and filtrate stands cooling and separates out solid, and filtering is dried in vacuo to obtain white solid i.e. 7- (benzene
Sulfonyl) -4- (1H- pyrazoles -4- bases) -7H- pyrrolo-es [2,3-d] pyrimidine (9.40g, yield 85.0%).MS m/z326[M+
1]+；1H NMR(400MHz,DMSO)δ9.48(s,20H),8.00–7.78(m,62H),7.72(s,1H),7.70(s,20H),
7.78–7.48(m,83H),7.21(s,21H),6.94(s,21H).
Embodiment 3
3- (cyano methyl) -3- (4- (7- benzenesulfonyls) -7H- pyrrolo-es [2,3-d] pyrimidine-4-yl) -1H pyrazoles -1-
Base) azetidine -1- t-butyl formates (VII) preparation
At room temperature, DMF (100mL), 7- (benzenesulfonyl) -4- (1H- pyrazoles -4- are sequentially added in 500mL reaction bulbs
Base) -7H- pyrrolo-es [2,3-d] pyrimidine (V, 9.40g, 0.029mol) and 3- (cyanomethylene) azetidine -1- formic acid uncles
Butyl ester (VI, 6.20g, 0.032mol), stirs and evenly mixs and DBU (0.221g, 1.452mmol) is added dropwise in backward reaction system, continues
It is stirred at room temperature 14 hours.When reacting complete, reactant mixture is quenched with water (150mL) and acetonitrile (100mL), gained mixture
Continue to stir 30min at room temperature, filtering collects solid, with acetonitrile-water mixture (2:3v/v, 20mL × 2) wash, 40-45
DEG C vacuum drying, obtain white solid be 3- (cyano methyl) -3- (4- (7- benzenesulfonyls) -7H- pyrrolo-es [2,3-d] pyrimidine -
4- yls) -1H pyrazol-1-yls) azetidine -1- t-butyl formates (13.86g, yield 92.0%).MS m/z 520[M+1
]+；1H NMR(400MHz,DMSO)δ9.48(s,1H),8.09(s,1H),7.94–7.80(m,2H),7.76(s,1H),7.71
(s,1H),7.68–7.60(m,2H),7.10(s,1H),5.66(s,1H),4.49–4.25(m,2H),4.25–3.93(m,2H),
2.77(s,2H),1.44(s,9H).
Embodiment 4
3- (cyanomethylene) -3- ((7- benzenesulfonyls) -7H- pyrrolo-es [2,3-d] pyrimidine-4-yl) -1H- pyrazoles -1-
Base) azetidine hydrochloride (VIII) preparation
In reaction bulb, sequentially add 3- (cyano methyl) -3- (4- (7- benzenesulfonyls) -7H- pyrrolo-es [2,3-d] pyrimidine -
4- yls) -1H pyrazol-1-yls) azetidine -1- t-butyl formates (VII, 10.00g, 0.019mol) and absolute ethyl alcohol
(50mL), is stirred at room temperature down, is slowly added dropwise after concentrated hydrochloric acid (1.5mL, 0.049mol), completion of dropping, heating reflux reaction 2h, instead
There is a small amount of solid to separate out during answering, TLC is monitored after completion of the reaction, and filtering, filter cake is eluted through absolute ethyl alcohol (5mL), at 50 DEG C
5h is dried in vacuo, 3- (cyanomethylene) -3- ((7- benzenesulfonyls) -7H- pyrrolo-es [2,3-d] pyrimidine-4-yl) -1H- is made
Pyrazol-1-yl) azetidine hydrochloride (8.49g, yield 98.0%).MS m/z 456[M+1]+；1H NMR(400MHz,
DMSO) δ 9.48 (s, 1H), 8.09 (s, 1H), 7.94-7.80 (m, 2H), 7.71 (d, J=5.2Hz, 2H), 7.68-7.60 (m,
2H),7.11(s,1H),5.62(s,1H),4.19–3.88(m,2H),3.88–3.64(m,2H),2.77(s,2H),1.99(s,
1H).
Embodiment 5
2- (1- (ethylsulfonyl) -3- (4- (7- benzenesulfonyl -7H- pyrrolo-es [2,3-d] pyrimidine-4-yl) -1H- pyrazoles -
1- yls) azetidine -3- bases) acetonitrile (IX) preparation
At 0-5 DEG C, successively by 3- (cyanomethylene) -3- ((7- benzenesulfonyls) -7H- pyrrolo-es [2,3-d] pyrimidine -
4- yls) -1H- pyrazol-1-yls) azetidine hydrochloride (VIII, 8.49g, 0.019mol), DIPEA
(7mL, 0.042mol) is dissolved in dichloromethane 50mL, and the dichloromethane (10mL) of ethyl sulfonic chloride (2mL, 0.021mol) is then added dropwise
Solution, room temperature is gradually increased to by gained reactant mixture, and is stirred at room temperature overnight, and reaction, which is finished, shifts reactant mixture
Into separatory funnel, washed with water (50mL × 2), merge organic phase, anhydrous Na2SO4Dry and be concentrated under reduced pressure into dry.Residue
Using 30mL isopropanols be beaten, obtain solid, filter, vacuum drying produce 2- (1- (ethylsulfonyl) -3- (4- (7- benzenesulfonyls -
7H- pyrrolo-es [2,3-d] pyrimidine-4-yl) -1H- pyrazol-1-yls) azetidine -3- bases) acetonitrile (9.23g, yield
95.0%).MS m/z512[M+1]+；1H NMR(400MHz,DMSO)δ9.48(s,1H),8.09(s,1H),7.95–7.80(m,
2H), 7.72 (d, J=10.2Hz, 2H), 7.68-7.61 (m, 2H), 7.11 (s, 1H), 5.65 (s, 1H), 4.04 (s, 1H),
(s, the 3H) of 3.77 (d, J=16.6Hz, 2H), 3.05 (d, J=17.9Hz, 3H), 2.77 (s, 2H), 1.32
Embodiment 6
1- (ethylsulfonyl) -3- [4- (7H- pyrrolo-es [2,3-d] pyrimidine-4-yl) -1H- pyrazol-1-yls] -3- azacyclo-s
The preparation of butane acetonitrile (Ba Rui replaces Buddhist nun, I)
To 2- (1- (ethylsulfonyl) -3- (4- (7- benzenesulfonyl -7H- pyrrolo-es [2,3-d] pyrimidine-4-yl) -1H- pyrroles
Azoles -1- bases) azetidine -3- bases) acetonitrile (IX, 9.23g, 0.018mol) 2- methyltetrahydrofurans (100mL) solution in,
Methanaminium, N,N,N-trimethyl-, fluoride trihydrate (7.95g, 0.054mol) is added, is stirred at reflux overnight.Reaction solution is concentrated under reduced pressure into dry, use
The ethanol of 40mL 90% is beaten to obtain crude product, and crude product is recrystallized using absolute ethyl alcohol, filtering, and absolute ethyl alcohol washing produces 1- after drying
(ethylsulfonyl) -3- [4- (7H- pyrrolo-es [2,3-d] pyrimidine-4-yl) -1H- pyrazol-1-yls] -3- azetidine acetonitriles
(5.43g, yield 81.2%).Collection of illustrative plates MS m/z 372 [M+H]+；1H-NMR (400Hz, DMSO-d6) δ 1.25 (t, 3H), 1.90
(s, 3H), 3.23 (q, 2H), 3.69 (s, 2H), 4.24 (d, 2H), 4.60 (d, 2H), 7.08 (dd, 1H), 7.62 (dd, 1H),
8.47 (s, 1H), 8.71 (s, 1H), 8.92 (s, 1H), 12.13 (s, 1H).HPLC contents：99.78%.
Claims (10)
1. a kind of Ba Rui replaces the preparation method of Buddhist nun, it is characterised in that comprise the following steps：
(1) with chloro- 7H- pyrrolo-es [2, the 3-d] pyrimidines (II) of 4- for raw material, it is substituted reaction system in the presence of a base with benzene sulfonyl chloride
Obtain intermediate 4- chloro- 7- (benzenesulfonyl) -7H- pyrrolo-es [2,3-d] pyrimidine (III)；
(2) in the presence of palladium catalytic system and alkali, intermediate III is with 4- pyrazoles pinacol borate through Suzuki coupling reaction systems
Obtain intermediate 7- (benzenesulfonyl) -4- (1H- pyrazoles -4- bases) -7H- pyrrolo-es [2,3-d] pyrimidine (V)；
(3) intermediate V and 3- (cyanomethylene) azetidine -1- t-butyl formates add through Michael in the presence of a catalyst
Intermediate 3- (cyano methyl) -3- (4- (7- benzenesulfonyls) -7H- pyrrolo-es [2,3-d] pyrimidine-4-yl) -1H is made into reaction
Pyrazol-1-yl) azetidine -1- t-butyl formates (VII)；
(4) intermediate 3- (cyanomethylene) -3- ((7- benzene sulfonyls are made in intermediate VII removing Boc protections under hydrochloric acid effect
Base) -7H- pyrrolo-es [2,3-d] pyrimidine-4-yl) -1H- pyrazol-1-yls) azetidine hydrochloride (VIII)；
(5) in the presence of alkali, intermediate compound I X is made through sulfonamide reaction in organic solvent with ethyl sulfonic chloride in intermediate VIII；
(6) intermediate compound I X removes benzene sulphur under the effect of one of Methanaminium, N,N,N-trimethyl-, fluoride or tetrabutyl ammonium fluoride or the trihydrate of the two
Acyl group is protected, and produces target product Ba Rui for Buddhist nun (I).
2. according to the method described in claim 1, wherein in the step (1), chloro- 7H- pyrrolo-es [2, the 3-d] pyrimidines (II) of 4-
Mol ratio with benzene sulfonyl chloride, alkali is 1：(1.1-1.4)：(1.1-1.3).
3. according to the method described in claim 1, wherein in the step (1), the alkali be selected from potassium tert-butoxide, sodium tert-butoxide,
NaH, potassium carbonate, sodium carbonate；One or more of the reaction dissolvent in tetrahydrofuran, acetonitrile, DMF；The reaction temperature is 0
DEG C-room temperature, the reaction time is 3-5h.
4. according to the method described in claim 1, wherein in the step (2), intermediate III and 4- pyrazoles pinacol borates
(IV) mol ratio is 1：The mol ratio of (1.1-1.3), intermediate III and palladium catalyst, alkali is 1：(0.01-0.03)：(2-
4)。
5. according to the method described in claim 1, wherein in the step (2), palladium catalytic system is selected from Pd (PPh3)4、Pd
(PPh3)4Cl2、Pd(PPh3)2Cl2、Pd(OAc)2/PPh3, alkali is selected from alkali carbonate or alkali metal hydrogencarbonate.
6. according to the method described in claim 1, wherein in the step (3), intermediate V and 3- (cyanomethylene) azacyclo-
Butane -1- t-butyl formates (VI), the mol ratio of catalyst are 1:(1-1.4)：(0.03-0.06).
7. according to the method described in claim 1, wherein in the step (3), catalyst be selected from DBU, alkali metal hydroxide,
Urea or thiocarbamide；One or more of the reaction dissolvent in DMF, acetonitrile, isopropanol.
8. according to the method described in claim 1, wherein in the step (4), the mol ratio of intermediate VII and hydrochloric acid is 1:
(2.2-2.6)；The hydrochloric acid is selected from concentrated hydrochloric acid or 15%-35% aqueous hydrochloric acid solution；Reaction dissolvent is selected from methanol, anhydrous second
One or more in alcohol, isopropanol, tetrahydrofuran.
9. according to the method described in claim 1, wherein in the step (5), the alkali is tertiary amine, preferably N, N- diisopropyls
Ethamine or triethylamine, more preferably DIPEA；The mol ratio of the intermediate VIII and ethyl sulfonic chloride, alkali is 1:
(1-1.3):(2.1-2.4)；One or more of the reaction dissolvent in dichloromethane, acetonitrile, tetrahydrofuran；The reaction temperature
Spend for 0 DEG C-room temperature；Reaction time 10-18h.
10. according to the method described in claim 1, wherein in the step (6), intermediate compound I X and Methanaminium, N,N,N-trimethyl-, fluoride or four fourths
The mol ratio of one of base ammonium fluoride or the trihydrate of the two is 1:(2.5-4)；Reaction dissolvent is selected from tetrahydrofuran or 2- methyl
Tetrahydrofuran；Reaction temperature is 60 DEG C-solvent reflux temperature；Reaction time 10-18.
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108586465A (en) * | 2017-12-13 | 2018-09-28 | 江苏中邦制药有限公司 | A kind of Ba Rui replaces the preparation method of Buddhist nun |
| CN110256441A (en) * | 2019-06-24 | 2019-09-20 | 江苏君若医药有限公司 | A kind of Ba Ruike replaces the preparation method of Buddhist nun |
| CN110799512A (en) * | 2017-06-22 | 2020-02-14 | 苏州科睿思制药有限公司 | Crystal form of Baricitinib and preparation method thereof |
| CN111999400A (en) * | 2020-07-15 | 2020-11-27 | 安徽联创生物医药股份有限公司 | Method for separating and determining impurities of bulk drugs of baricitinib by using HPLC (high performance liquid chromatography) |
| CN113582998A (en) * | 2021-06-25 | 2021-11-02 | 江苏君若药业有限公司 | Preparation of 4- (1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine |
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| CN113582998A (en) * | 2021-06-25 | 2021-11-02 | 江苏君若药业有限公司 | Preparation of 4- (1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine |
| CN113788834A (en) * | 2021-09-18 | 2021-12-14 | 奥思恩(河南)新材料科技有限公司 | Preparation method of 2, 4-dichloro-6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidine hydrochloride |
| CN115124537A (en) * | 2022-07-13 | 2022-09-30 | 山东大学 | Preparation method of JAK inhibitor britinib |
| CN115417876A (en) * | 2022-09-20 | 2022-12-02 | 山东新时代药业有限公司 | Baritinib intermediate compound |
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