CN107176955B - A kind of Ba Rui replaces the preparation method of Buddhist nun - Google Patents
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Abstract
The invention discloses the preparation methods that a kind of Ba Rui replaces Buddhist nun, with chloro- 7H- pyrrolo- [2, the 3-d] pyrimidine (II) of 4- for raw material, are substituted in the presence of a base with benzene sulfonyl chloride and react obtained intermediate III；Then in the presence of palladium catalytic system and alkali, intermediate III and 4- pyrazoles pinacol borate are through the obtained intermediate V of Suzuki coupling reaction；Then intermediate VII is made through Michael addition reaction in the presence of a catalyst in intermediate V and 3- (cyanomethylene) azetidine -1- t-butyl formate；Then intermediate VII removing Boc under hydrochloric acid effect, which is protected, is made intermediate VIII；Then in the presence of a base, intermediate compound I X is made through sulfonamide reaction in organic solvent in intermediate VIII and ethyl sulfonic chloride；Last intermediate compound I X removing benzenesulfonyl protection under the effect of one of the trihydrate of Methanaminium, N,N,N-trimethyl-, fluoride or tetrabutyl ammonium fluoride or both to get Ba Rui replaces Buddhist nun (I).Compared with prior art, the method for the invention has the advantages that raw material is easy to get, is low in cost, product yield is high and easy to industrialized production.
Description
Technical field
The present invention relates to pharmaceutical synthesis fields, and in particular to a kind of Pyrrolopyrimidine JAK inhibitor medicaments Ba Rui replaces Buddhist nun
Preparation Method And Their Intermediate compound.
Background technique
Ba Rui is to be total to by gift come pharmacy collaboration partner Incyte company for Buddhist nun (Baricitinib, Olumiant, 1)
With a kind of selectivity JAK1 and JAK2 inhibitor of exploitation, the cell of a variety of inflammatory cytokines such as IL-6 and IL-23 can be inhibited
Interior signal transduction, entitled 1- (ethylsulfonyl) -3- [4- (7H- pyrrolo- [2,3-d] the pyrimidine-4-yl) -1H- pyrazoles -1- of chemistry
Base] -3- azetidine acetonitrile, shown in structural formula such as formula (I).The product were used in treatment extremely in 2017 by European Union's approval
Severe rheumatoid arthritis, the adult that current rheumatoid arthritis agents are not reacted or do not tolerated, can be used as
Single medicine uses, and can also be used together with widely used methotrexate (MTX).
Ba Rui is used to prepare disclosed in the prior art mainly to be had for the method for Buddhist nun:
(1) Incyte company reports the synthetic route that a Ba Rui replaces Buddhist nun in patent WO2009114512A1, as follows
It is shown:
Meanwhile the patent also discloses and uses N- oxy acid methyl neopentyl 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 route is tediously long, NaH has been used in the N protection reaction of 4- chlorine pyrrolo- [2,3-d] pyrimidine (2), is grasped
It is subsequent when making complexity, and carrying out SEM protection can be just deprotected through two-step reaction, it is more troublesome, the Suzuki of intermediate 3 and 4
Coupling reaction need to just can be carried out after pyrazoles NH is protected, and thus also add subsequent deprotection operation, cause gross production rate inclined
It is low.In addition, SEM-Cl or POM-Cl are expensive, lead to that the production cost increases.
(2) CN105294699A also discloses that a kind of Ba Rui replaces the synthesis technology of Buddhist nun:
The N protecting group of N protecting group and azetidine in technique adjustment Pyrrolopyrimidin phenazine ring is 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 in Pyrrolopyrimidin phenazine ring influences yield by sulfonylation.
(3) CN105541891A also discloses that a kind of Ba Rui replaces the synthesis technology of Buddhist nun:
The technique directly carries out Michael addition reaction with the azetidine raw material 10 that ethylsulfonyl replaces, to make
It obtains the intermediate 11 in Suzuki coupling reaction not needing to carry out amido protecting and subsequent deprotection, shortens reaction step,
But the separation of borate intermediate 11 is chromatographed using column, and borate may be adsorbed because of partial hydrolysis for boric acid, be caused
Certain product loss.
Summary of the invention
Aiming at the problems existing in the prior art, the object of the present invention is to provide the preparation methods that a kind of Ba Rui replaces Buddhist nun, originally
Process route raw material provided by inventing 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, includes the following steps:
(1) it with chloro- 7H- pyrrolo- [2, the 3-d] pyrimidine (II) of 4- for raw material, is substituted in the presence of a base with benzene sulfonyl chloride anti-
Intermediate 4- chloro- 7- (benzenesulfonyl) -7H- pyrrolo- [2,3-d] pyrimidine (III) should be made；
(2) in the presence of palladium catalytic system and alkali, intermediate III and 4- pyrazoles pinacol borate are coupled instead through Suzuki
Intermediate 7- (benzenesulfonyl) -4- (1H- pyrazoles -4- base) -7H- pyrrolo- [2,3-d] pyrimidine (V) should be made；
(3) intermediate V and 3- (cyanomethylene) azetidine -1- t-butyl formate are in the presence of a catalyst through mikey
Intermediate 3- (cyano methyl) -3- (4- (7- benzenesulfonyl) -7H- pyrrolo- [2,3-d] pyrimidine -4- is made for addition reaction in you
Base) -1H pyrazol-1-yl) azetidine -1- t-butyl formate (VII)；
(4) intermediate VII removing Boc under hydrochloric acid effect, which is protected, is made intermediate 3- (cyanomethylene) -3- ((7- benzene
Sulfonyl) -7H- pyrrolo- [2,3-d] pyrimidine-4-yl) -1H- pyrazol-1-yl) azetidine hydrochloride (VIII)；
(5) in the presence of alkali, intermediate is made through sulfonamide reaction in organic solvent in intermediate VIII and ethyl sulfonic chloride
IX；
(6) intermediate compound I X is removed under the effect of one of trihydrate of Methanaminium, N,N,N-trimethyl-, fluoride or tetrabutyl ammonium fluoride or both
Benzenesulfonyl protection replaces Buddhist nun (I) to get target product Ba Rui.
Reaction equation is as follows:
In step (1), the molar ratio of chloro- 7H- pyrrolo- [2, the 3-d] pyrimidine (II) of 4- and benzene sulfonyl chloride is 1:
(1.1-1.4)；The alkali can be selected from potassium tert-butoxide, sodium tert-butoxide, NaH, potassium carbonate, sodium carbonate；The chloro- 7H- pyrrolo- of 4-
The dosage molar 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, reaction time 3-5h.
In step (2), the molar 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 the molar ratio of palladium catalyst, 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；
Reaction dissolvent is selected from one or more of DMF, acetonitrile, isopropanol；The molar ratio of the intermediate V and catalyst is 1:
(0.03-0.06)。
In step (4), the molar ratio of the intermediate VII and hydrochloric acid is 1:(2.2-2.6)；Dense salt can be used in the hydrochloric acid
The aqueous hydrochloric acid solution of acid or 15%-35%；Reaction dissolvent be selected from one of methanol, dehydrated alcohol, isopropanol, tetrahydrofuran or
It is several, preferred dehydrated alcohol.
In step (5), the alkali is tertiary amine, preferably n,N-diisopropylethylamine or triethylamine, more preferable N, N- diisopropyl
Base ethamine；The molar 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 of methylene chloride, acetonitrile, tetrahydrofuran；The reaction temperature is 0 DEG C-room temperature；Reaction time 10-18h.
In step (6), the trihydrate of the intermediate compound I X and Methanaminium, N,N,N-trimethyl-, fluoride or tetrabutyl ammonium fluoride or both it
One molar ratio is 1:(2.5-4)；Reaction dissolvent is selected from tetrahydrofuran or 2- methyltetrahydrofuran；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 the preparation method of Buddhist nun (I) there is raw material to be easy to get, is at low cost
Honest and clean, simple process, mild condition, the advantage that operation is convenient, product yield is high and easy to industrialized production.
Specific embodiment
Below in conjunction with specific embodiment, the present invention is further elaborated.
Embodiment 1
The preparation of 4- chloro- 7- (benzenesulfonyl) -7H- pyrrolo- [2,3-d] pyrimidine (III)
Chloro- 7H- pyrrolo- [2, the 3-d] pyrimidine (II, 15.00g, 0.098mol) of 4- is dissolved in 400mL THF, then plus
Enter potassium tert-butoxide (13.70g, 0.122mol), 20min is stirred at room temperature in reaction mixture, when the reaction is exothermic, using ice-water bath
Benzene sulfonyl chloride (15.6mL, 0.122mol) is added dropwise into mixed liquor in supplement heat rejecter, drips and finishes stirring 3h.Stop reaction, decompression removal
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- [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- base) -7H- pyrrolo- [2,3-d] pyrimidine (V)
At room temperature, by 4- chloro- 7- (phenyl sulfonyl) -7H- pyrrolo- [2,3-d] pyrimidine (III, 10.00g,
0.034mol), water (50mL) and potassium carbonate (14.12g, 0.102mol) are added in 500mL reaction flask, and 4- pyrazoles boron is then added
Sour pinacol ester (IV, 7.93g, 0.041mol), DMF (100mL) and Pd (PPh3)4(0.59g, 0.511mmol).Reaction is mixed
It closes object and is heated to 80-85 DEG C, then insulated and stirred 4 hours.It is monitored and is reacted by TLC, after fully reacting, added into reaction flask
500mL mixture of ice and water stirs 20min, and solid is precipitated, and dry crude product after filtering, then crude product is added using 50mL isopropanol
Heat of solution is filtered to remove insoluble matter while hot, and filtrate stands cooling precipitation solid, and filtering is dried in vacuo to obtain white solid i.e. 7- (benzene
Sulfonyl) -4- (1H- pyrazoles -4- base) -7H- pyrrolo- [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- benzenesulfonyl) -7H- pyrrolo- [2,3-d] pyrimidine-4-yl) -1H pyrazoles -1-
Base) azetidine -1- t-butyl formate (VII) preparation
At room temperature, DMF (100mL), 7- (benzenesulfonyl) -4- (1H- pyrazoles -4- are sequentially added in 500mL reaction flask
Base) -7H- pyrrolo- [2,3-d] pyrimidine (V, 9.40g, 0.029mol) and 3- (cyanomethylene) azetidine -1- formic acid uncle
DBU (0.221g, 1.452mmol) is added dropwise into reaction system after stirring and evenly mixing in butyl ester (VI, 6.20g, 0.032mol), continues
It is stirred at room temperature 14 hours.When fully reacting, reaction mixture is quenched with water (150mL) and acetonitrile (100mL), gained mixture
Continue to stir 30min at room temperature, solid is collected in filtering, is washed with acetonitrile-water mixture (2:3v/v, 20mL × 2), 40-45
DEG C vacuum drying, obtain white solid, that is, 3- (cyano methyl) -3- (4- (7- benzenesulfonyl) -7H- pyrrolo- [2,3-d] pyrimidine -
4- yl) -1H pyrazol-1-yl) azetidine -1- t-butyl formate (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- benzenesulfonyl) -7H- pyrrolo- [2,3-d] pyrimidine-4-yl) -1H- pyrazoles -1-
Base) azetidine hydrochloride (VIII) preparation
In reaction flask, 3- (cyano methyl) -3- (4- (7- benzenesulfonyl) -7H- pyrrolo- [2,3-d] pyrimidine-is sequentially added
4- yl) -1H pyrazol-1-yl) azetidine -1- t-butyl formate (VII, 10.00g, 0.019mol) and dehydrated alcohol
(50mL), is stirred at room temperature down, and concentrated hydrochloric acid (1.5mL, 0.049mol) is slowly added dropwise, after being added dropwise, heating reflux reaction 2h, instead
There should be in the process a small amount of solid to be precipitated, TLC is monitored after completion of the reaction, and filtering, filter cake is eluted through dehydrated alcohol (5mL), at 50 DEG C
It is dried in vacuo 5h, 3- (cyanomethylene) -3- ((7- benzenesulfonyl) -7H- pyrrolo- [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- [2,3-d] pyrimidine-4-yl) -1H- pyrazoles -
1- yl) azetidine -3- base) acetonitrile (IX) preparation
At 0-5 DEG C, successively by 3- (cyanomethylene) -3- ((7- benzenesulfonyl) -7H- pyrrolo- [2,3-d] pyrimidine -
4- yl) -1H- pyrazol-1-yl) azetidine hydrochloride (VIII, 8.49g, 0.019mol), n,N-diisopropylethylamine
(7mL, 0.042mol) is dissolved in methylene chloride 50mL, and the methylene chloride (10mL) of ethyl sulfonic chloride (2mL, 0.021mol) is then added dropwise
Gained reaction mixture is gradually increased to room temperature, and is stirred at room temperature overnight by solution, and end of reaction shifts reaction mixture
It into separatory funnel, is washed with water (50mL × 2), merges organic phase, anhydrous Na2SO4It dries and is concentrated to dryness.Residue
It is beaten using 30mL isopropanol, obtains solid, filtered, is dried in vacuo up to 2- (1- (ethylsulfonyl) -3- (4- (7- benzenesulfonyl -
7H- pyrrolo- [2,3-d] pyrimidine-4-yl) -1H- pyrazol-1-yl) azetidine -3- base) 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),
3.77 (d, J=16.6Hz, 2H), 3.05 (d, J=17.9Hz, 3H), 2.77 (s, 2H), 1.32 (s, 3H)
Embodiment 6
1- (ethylsulfonyl) -3- [4- (7H- pyrrolo- [2,3-d] pyrimidine-4-yl) -1H- pyrazol-1-yl] -3- azacyclo-
The preparation of butane acetonitrile (Ba Rui replaces Buddhist nun, I)
To 2- (1- (ethylsulfonyl) -3- (4- (7- benzenesulfonyl -7H- pyrrolo- [2,3-d] pyrimidine-4-yl) -1H- pyrrole
Azoles -1- base) azetidine -3- base) acetonitrile (IX, 9.23g, 0.018mol) 2- methyltetrahydrofuran (100mL) solution in,
It is added Methanaminium, N,N,N-trimethyl-, fluoride trihydrate (7.95g, 0.054mol), is stirred at reflux overnight.Reaction solution is concentrated to dryness, and is used
90% ethyl alcohol of 40mL is beaten to obtain crude product, and crude product is recrystallized using dehydrated alcohol, filtering, dehydrated alcohol washing, up to 1- after drying
(ethylsulfonyl) -3- [4- (7H- pyrrolo- [2,3-d] pyrimidine-4-yl) -1H- pyrazol-1-yl] -3- azetidine acetonitrile
(5.43g, yield 81.2%).Map 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 content: 99.78%.
Claims (12)
1. the preparation method that a kind of Ba Rui replaces Buddhist nun, which comprises the steps of:
(1) system of reacting is substituted with benzene sulfonyl chloride for raw material with chloro- 7H- pyrrolo- [2, the 3-d] pyrimidine (II) of 4- in the presence of a base
Obtain the chloro- 7- of intermediate 4- (benzenesulfonyl) -7H- pyrrolo- [2,3-d] pyrimidine (III)；
(2) in the presence of palladium catalytic system and alkali, intermediate III and 4- pyrazoles pinacol borate (IV) are coupled instead through Suzuki
Intermediate 7- (benzenesulfonyl) -4- (1H- pyrazoles -4- base) -7H- pyrrolo- [2,3-d] pyrimidine (V) should be made；
(3) intermediate V and 3- (cyanomethylene) azetidine -1- t-butyl formate (VI) are in the presence of a catalyst through mikey
Intermediate 3- (cyano methyl) -3- (4- (7- benzenesulfonyl) -7H- pyrrolo- [2,3-d] pyrimidine -4- is made for addition reaction in you
Base) -1H- pyrazol-1-yl) azetidine -1- t-butyl formate (VII)；Wherein, the catalyst is selected from selected from DBU, alkali gold
Belong to hydroxide, urea or thiocarbamide；
(4) intermediate VII removing Boc under hydrochloric acid effect, which is protected, is made intermediate 3- (cyanomethylene) -3- ((7- benzene sulfonyl
Base) -7H- pyrrolo- [2,3-d] pyrimidine-4-yl) -1H- pyrazol-1-yl) azetidine hydrochloride (VIII)；
(5) in the presence of alkali, intermediate compound I X is made through sulfonamide reaction in organic solvent in intermediate VIII and ethyl sulfonic chloride；
(6) intermediate compound I X removes benzene sulphur under the effect of one of trihydrate of Methanaminium, N,N,N-trimethyl-, fluoride or tetrabutyl ammonium fluoride or both
Acyl group protection replaces Buddhist nun (I) to get target product Ba Rui.
2. according to the method described in claim 1, wherein in the step (1), chloro- 7H- pyrrolo- [2, the 3-d] pyrimidine (II) of 4-
Molar 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；Reaction dissolvent is selected from one or more of tetrahydrofuran, acetonitrile, DMF；The reaction temperature is 0
DEG C-room temperature, reaction time 3-5h.
4. according to the method described in claim 1, wherein in the step (2), intermediate III and 4- pyrazoles pinacol borate
(IV) molar ratio is 1:(1.1-1.3), the molar ratio of intermediate III and palladium catalyst, alkali is 1:(0.01-0.03): (2-
4)。
5. according to the method described in claim 1, palladium catalytic system is selected from Pd (PPh wherein in the step (2)3)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 formate (VI), catalyst molar ratio be 1:(1-1.4): (0.03-0.06).
7. according to the method described in claim 1, catalyst is selected from DBU, urea or thiocarbamide wherein in the step (3)；Reaction
Solvent is selected from one or more of DMF, acetonitrile, isopropanol.
8. according to the method described in claim 1, the molar ratio of intermediate VII and hydrochloric acid is 1 wherein in the step (4):
(2.2-2.6)；The hydrochloric acid is selected from concentrated hydrochloric acid or the aqueous hydrochloric acid solution of 15%-35%；Reaction dissolvent is selected from methanol, anhydrous second
One or more of alcohol, isopropanol, tetrahydrofuran.
9. according to the method described in claim 1, the alkali is tertiary amine wherein in the step (5)；The intermediate VIII with
Ethyl sulfonic chloride, alkali molar ratio be 1:(1-1.3): (2.1-2.4)；Reaction dissolvent is in methylene chloride, acetonitrile, tetrahydrofuran
One or more；The reaction temperature is 0 DEG C-room temperature；Reaction time 10-18h.
10. according to the method described in claim 9, wherein the alkali is selected from n,N-diisopropylethylamine or triethylamine.
11. according to the method described in claim 10, wherein the alkali is selected from n,N-diisopropylethylamine.
12. 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 molar ratio of one of the trihydrate of base ammonium fluoride or both 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 10-18h.
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| CN108129482A (en) * | 2017-12-13 | 2018-06-08 | 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 |
| CN111999400B (en) * | 2020-07-15 | 2022-07-01 | 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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