CN110194776A - A kind of synthetic method of Rui Lugeli - Google Patents
A kind of synthetic method of Rui Lugeli Download PDFInfo
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- CN110194776A CN110194776A CN201910568929.7A CN201910568929A CN110194776A CN 110194776 A CN110194776 A CN 110194776A CN 201910568929 A CN201910568929 A CN 201910568929A CN 110194776 A CN110194776 A CN 110194776A
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Abstract
The present invention provides a kind of methods for preparing Rui Lugeli midbody compound 8, the described method comprises the following steps: (a) compound 2 and N, and the reaction of N'- carbonyl dimidazoles obtains compound 3；(b) compound 3 and 2, bis- fluorobenzyl chloride of 6- reaction, obtains compound 4；(c) compound 4 is reacted with 3- amino -6- methoxyl group pyridazine, obtains compound 5；(d) compound 5 and N, the reaction of N'- carbonyl dimidazoles, obtain compound 6；(e) compound 6 is reacted with N- bromo-succinimide, azodiisobutyronitrile, obtains compound 7；(f) compound 7 is reacted with dimethylamine hydrochloride, obtains compound 8.The present invention also provides a kind of methods for preparing Rui Lugeli, the described method comprises the following steps: compound 8 made from (g) above method reacts under catalyst with hydrogen, obtains compound 9；(h) compound 9 and N, N'- carbonyl dimidazoles, methoxy amine hydrochlorate reaction, obtain Rui Lugeli.The route that the method provided by the invention for preparing Rui Lugeli is coupled again using first closed loop, operation is simpler, and side reaction is few, and reaction condition is mild, and yield, purity is high, product purify well, and commercial size metaplasia is suitble to produce.
Description
Technical field
The present invention relates to pharmaceutical synthesis field more particularly to a kind of synthetic methods of Rui Lugeli.
Background technique
The secretion of tethelin is periphery hormone, Yi Jitong by being secreted from the target organ of various hormones
The secretion from hypothalamus lower part-adjusting hormone is crossed, feedback control is carried out.At present, it has been found that belong to above-mentioned hormone
There are nine kinds, for example, [GnRH, sometimes referred to as LH-RH (promote yellow for thyrotrophin-releasing hormone (TRH) and gonadotropin-releasing hormone
Voxel releasing hormone)].The secretion of these hormones is corresponding receptor related, and therefore, searching out being capable of specificity, selectivity
Ground acts on the antagonist or agonist of this receptor, it will be able to realize the secretion to specific tethelin.
Rui Lugeli (Relugolix), No. CAS is 737789-87-6, and chemical name is N- (4- (1- (2,6- difluoro benzyls
Base) -5- ((dimethylamino) methyl) -3- (6- methoxyl group -3- pyridazinyl) -2,4- dioxo -1,2,3,4- thiophane simultaneously [2,
3-d] pyrimidine -6- base) phenyl)-N'- methoxyl group urea.It is by Myovant company and military field medicine company (Takeda) joint development
A kind of new drug is a kind of small molecule gonadoliberin (GnRH) receptor antagonist, potential to be used for fibroma uteri, son
The indications such as endometriosis, prostate cancer.Currently, relugolix is nearly the 1600 of 1 phase, 2 phases and 3 clinical trial phases
It is assessed in name research participant.Relugolix at daily oral one time, can reduce rapidly women estrogen and
Progesterone level.Military field pharmacy by it is a series of Japan carry out the clinical III phases study, compared Relugolix and
The safety of the fibrosis of uterus of leuprorelin (Leuprorelin) treatment menorrhalgia and validity and above-mentioned two medicine
Object is treating safety and validity on pain symptom related with fibrosis of uterus, finally confirms that relugolix is used for
The safety and validity of fibroma uteri.In addition, military field pharmacy has carried out mullerianosis and the forefront of relugolix
The II phase clinical research of gland cancer, it was demonstrated that relugolix can significantly mitigate pain caused by mullerianosis, can also reduce serum
Testosterone is horizontal to castration and significantly reduces prostate-specific antigen (PSA).
Patent CN104703992 discloses a kind of method for preparing Relugolix, and synthetic route is as follows.This method will
Compound 2 (CAS:174072-89-0) successively obtains intermediate product 3 '~7 ', then in using first coupling, again by the way of closed loop
Between product 7 ' be raw material, successively be made intermediate product 8,9, finally obtain product Relugolix.But this method is using first even
The mode of connection, again closed loop, severe reaction conditions need to react under conditions of heating, pressurization, to the more demanding of equipment.
So developing a kind of preparation at low cost, yield is high, reaction condition is mild, equipment requirement is low, product purity is high
The method of Rui Lugeli has very big application value.
Summary of the invention
The purpose of the present invention is to provide a kind of simple, efficient methods, to prepare Rui Lugeli.
The present invention provides a kind of methods for preparing Rui Lugeli midbody compound 8, the described method comprises the following steps:
(a) compound 2 and N, the reaction of N'- carbonyl dimidazoles, obtain compound 3；
(b) compound 3 and 2, bis- fluorobenzyl chloride of 6- reaction, obtains compound 4；
(c) compound 4 is reacted with 3- amino -6- methoxyl group pyridazine, obtains compound 5；
(d) compound 5 and N, the reaction of N'- carbonyl dimidazoles, obtain compound 6；
(e) compound 6 is reacted with N- bromo-succinimide, azodiisobutyronitrile, obtains compound 7；
(f) compound 7 is reacted with dimethylamine hydrochloride, obtains compound 8；
Wherein, the structure of compound 2 isThe structure of compound 3 isThe structure of compound 4 isThe structure of compound 5 isThe structure of compound 6 isThe structure of compound 7 isThe structure of compound 8 is
Further, in step (a), the molar ratio of the compound 2 and N, N'- carbonyl dimidazoles is 1:(1~3), instead
Answering temperature is 60~80 DEG C, and the reaction time is 1~3h；Reaction dissolvent is organic solvent；
And/or in step (b), compound 3 and 2, the molar ratio of bis- fluorobenzyl chloride of 6- is 1:(1.0~2.0)；Reaction be
It is carried out under the action of alkali；Reaction dissolvent is organic solvent；Reaction temperature is 80~120 DEG C, and the reaction time is 3~7h；
And/or in step (c), the molar ratio of compound 4 and 3- amino -6- methoxyl group pyridazine is 1:(1~1.5)；Reaction
It carries out in the presence of alkali；Reaction dissolvent is organic solvent；Reaction temperature is 50~70 DEG C, and the reaction time is 2~4h；
And/or in step (d), compound 5 and N, the molar ratio of N'- carbonyl dimidazoles are 1:(1~3)；Reaction dissolvent is
Organic solvent；Reaction temperature is 60~80 DEG C, and the reaction time is 3~7h；
And/or in step (e), the molar ratio of compound 6 and N- bromo-succinimide, azodiisobutyronitrile is 1:
(1.00~1.20): (0.08~0.20)；Reaction dissolvent is organic solvent；Reaction temperature is reflux temperature, the reaction time is 3~
5h；
And/or in step (f), the molar ratio of compound 7 and dimethylamine hydrochloride is 1:(1.0~2.0)；The reaction
It carries out in the presence of base；Reaction dissolvent is organic solvent；Reaction temperature is 60~100 DEG C, 3~7h of reaction time.
Further, in step (a), the molar ratio of the compound 2 and N, N'- carbonyl dimidazoles is 1:2, reaction temperature
It is 70 DEG C, reaction time 2h；Reaction dissolvent is tetrahydrofuran；
And/or in step (b), compound 3 and 2, the molar ratio of bis- fluorobenzyl chloride of 6- is 1:1.3；The alkali is N, and N- bis- is different
The molar ratio of propylethylamine, alkali and compound 3 is 2.5:1；Reaction dissolvent is N,N-dimethylformamide；Reaction temperature is 100
DEG C, reaction time 5h；
And/or in step (c), the molar ratio of compound 4 and 3- amino -6- methoxyl group pyridazine is 1:1.2；The alkali is
The molar ratio of potassium carbonate, alkali and compound 4 is 2.5:1；Reaction dissolvent is N,N-dimethylformamide；Reaction temperature is 60 DEG C,
Reaction time is 3h；
And/or in step (d), compound 5 and N, the molar ratio of N'- carbonyl dimidazoles are 1:2；Reaction dissolvent is tetrahydro
Furans；Reaction temperature is 70 DEG C, reaction time 5h；
And/or in step (e), the molar ratio of compound 6 and N- bromo-succinimide, azodiisobutyronitrile is 1:
1.08:0.10；Reaction dissolvent is carbon tetrachloride；Reaction time is 4h；
And/or in step (f), the molar ratio of compound 7 and dimethylamine hydrochloride is 1:1.5；The alkali is potassium carbonate,
The molar ratio of alkali and compound 7 is 4:1；Reaction dissolvent is N,N-dimethylformamide；Reaction temperature is 80 DEG C, the reaction time
5h。
Further, compound 2 the preparation method comprises the following steps:
(1) 4- nitro propiophenone is reacted with ethyl cyanoacetate, sulphur powder, obtains compound 1；
(2) compound 1 is reacted with alkali, obtains compound 2；
Wherein, the structure of compound 1 is
Further, in step (1), 4- nitro propiophenone, ethyl cyanoacetate, sulphur powder molar ratio be 1:(0.8~
1.2): (0.8~1.2)；The reaction carries out in the presence of alkali；The temperature of the reaction is 40~60 DEG C, when reaction
Between be 4~8h, reaction dissolvent is organic solvent；
And/or in step (2), the alkali is sodium hydroxide solution, the quality volume of compound 1 and sodium hydroxide solution
Than for 153g:(800~1200) mL；Reaction temperature is reflux temperature, and the reaction time is 3.0~4.0h；Reaction dissolvent is organic
Solvent；
Preferably, in step (1), 4- nitro propiophenone, cyan-acetic ester, sulphur powder molar ratio be 1:1:1；The alkali
For triethylamine, the molar ratio of the alkali and 4- nitro propiophenone is 1:1；The temperature of the reaction is 50 DEG C, reaction time 6h；
Reaction dissolvent is ethyl alcohol；
And/or in step (2), the concentration of the sodium hydroxide solution is 2mol/L, compound 1 and sodium hydroxide solution
Mass volume ratio be 153g:1000mL；Reaction temperature is reflux temperature, reaction time 3.5h；Reaction dissolvent is ethyl alcohol.
Further, the method also includes purification steps, wherein in step (a), method of purification are as follows: after the reaction
Ethyl acetate and water are added in system, extracts liquid separation, takes organic phase, successively with the hydrochloric acid of 1mol/L, saturated common salt water washing, takes
Organic phase, it is dry to get；
In step (b), method of purification are as follows: the system after answering is negated, water is added, is extracted with ethyl acetate, takes organic phase, according to
The secondary hydrochloric acid with 1mol/L, saturated common salt water washing obtain crude product, then the second for being 1:2 with volume ratio after taking organic phase, concentration dry
The mixed solution of alcohol and methylene chloride to crude product recrystallize to get；
In step (c), method of purification are as follows: the system after answering is negated, water is added, is extracted with ethyl acetate, takes organic phase, according to
It is secondary to use 1mol/L hydrochloric acid, saturated common salt water washing, take organic phase, it is dry to get；
In step (d), method of purification are as follows: negate the system after answering, l ethyl acetate and water is added, extract liquid separation, take organic
Phase successively uses 1mol/L hydrochloric acid, saturated common salt water washing, obtains crude product after taking organic phase, concentration dry, then use methyl tertiary butyl ether(MTBE)
Mashing purifying, filtering, take solid to get；
In step (e), method of purification are as follows: the system after answering is negated, water is added, washs, takes organic phase, it is dry, crude product is obtained, so
The ethyl alcohol and methylene chloride that are afterwards 1:1 with volume ratio mixed solution recrystallization to get；
In step (f), method of purification are as follows: negate the system after answering, water and ethyl acetate is added, extraction takes organic phase, uses
Saturated common salt water washing, takes organic phase, it is dry to get.
The present invention also provides a kind of methods for preparing Rui Lugeli, the described method comprises the following steps:
(g) compound 8 made from the above method reacts under catalyst with hydrogen, obtains compound 9；
(h) compound 9 and N, N'- carbonyl dimidazoles, methoxy amine hydrochlorate reaction, obtain Rui Lugeli；
Wherein, the structure of compound 9 isThe structure of Rui Lugeli is
Further, in step (g), the reaction is carried out in atmosphere of hydrogen, the quality of compound 8 and catalyst
Than for 10:(0.5~3.0), the catalyst is Pd/C；Reaction dissolvent is organic solvent；Reaction temperature is room temperature, reaction time
4~8h；
And/or in step (h), reaction process are as follows: compound 9 and N, N'- carbonyl dimidazoles are first anti-in the presence of alkali
It answers, wherein reaction temperature is room temperature, and the reaction time is 30 minutes；Then reaction system is added in methoxy amine hydrochlorate again, after
Continuous reaction, wherein reaction temperature is 50 DEG C, reaction time 4.5h.
Further, in step (g), the mass ratio of compound 8 and catalyst is 10:1.0, and the catalyst is 10%
Pd/C；Reaction dissolvent is ethyl alcohol；Reaction time 6h；
And/or in step (h), compound 9 and N, N'- carbonyl dimidazoles, methoxy amine hydrochlorate molar ratio be 1:2:
5, the alkali is n,N-diisopropylethylamine, and the molar ratio of alkali and compound 9 is 1:2；Reaction dissolvent is acetonitrile.
Further, the method also includes purification steps, wherein in step (g), method of purification are as follows: negate after answering
System, filtering, takes filtrate to be concentrated, and 2 times of liquid volume after concentration of n-hexane, stirring and crystallizing 2h is added, and filtering takes solid, i.e.,
?；
In step (h), method of purification are as follows: the system after answering is negated, water, stirring and crystallizing 1h is added, filtering takes solid, then
With volume ratio be 1:1 ethyl alcohol and methylene chloride mixed solution be beaten purifying, filtering, take solid to get.
Mashing purifying will contain the solution of solid matter to be purified, stirring a period of time, then filter, separate.It is to utilize
The method of the different solubility purification of substance to be purified and impurity in a solvent, solvent generally select substance dissolubility to be purified compared with
Difference, the preferable solvent of impurity dissolubility.
Room temperature refers to 20~25 DEG C.
Product quality/theoretical calculation product quality × 100% for yield=actually obtain.
It is experimentally confirmed, the route that the method provided by the invention for preparing Rui Lugeli is coupled again using first closed loop, behaviour
Work is simpler, and side reaction is few, and reaction condition is mild, and yield, purity is high, product purify well, and commercial size metaplasia is suitble to produce.
Obviously, above content according to the present invention is not being departed from according to the ordinary technical knowledge and customary means of this field
Under the premise of the above-mentioned basic fundamental thought of the present invention, the modification, replacement or change of other diversified forms can also be made.
Above content of the invention is described in further detail by the following examples, but this should not be interpreted as to this
The range for inventing above-mentioned theme is only limitted to embodiment below.All technologies realized based on above content of the present invention belong to this
The range of invention.
Specific embodiment
The raw materials used in the present invention and reagent are known product, as obtained by purchase commercial product.
The synthesis of 1 Rui Lugeli of embodiment
According to following synthetic route, prepare compound Rui Lugeli:
Steps 1 and 2-amino-4- methyl-5- (4- nitrobenzophenone)-3- thiophene carboxylate (compound 1) synthesis:
4- nitro propiophenone (30g, 0.17mol), ethyl cyanoacetate (19.2g, 0.17mol) and ethyl alcohol (200ml) are added
Enter into reaction flask, stirring and dissolving, adds triethylamine (17.2g, 0.17mol) and sulphur powder (5.4g, 0.17mol), be heated to
50 DEG C of reactions 6h, TLC monitor fully reacting.Concentration removes ethyl alcohol, and 300ml ethyl acetate is added in residue, is saturated with 100ml
Saline solution extraction, concentration organic phase obtain crude product.Ethyl acetate/n-hexane (200ml/200ml) crystallization purifying is used again, is filtered,
2- amino -4- methyl -5- (4- nitrobenzophenone) -3- thiophene carboxylate (compound 1) 35.4g, yield 69% are obtained after drying.
The synthesis of step 2,2- amino -4- methyl -5- (4- nitrobenzophenone)-thenoic acid (compound 2):
By 2- amino -4- methyl -5- (4- nitrobenzophenone) -3- thiophene carboxylate (153g, 0.5mol) made from step 1
It is dissolved in ethyl alcohol (1200ml), is added 2N sodium hydroxide solution (1000ml), back flow reaction 3.5h, TLC monitor fully reacting.It is dense
Contracting removes ethyl alcohol, and with methyl tertiary butyl ether(MTBE) (300mlX2) extracting impurities, water layer 2N hydrochloric acid tune PH is 3~4, and solid, mistake is precipitated
Filter, filter cake are successively washed with water (500mlX2), n-hexane (500ml), obtain 2- amino -4- methyl -5- (4- nitro after dry
Phenyl)-thenoic acid (compound 2) 132.2g, yield 95%.
Step 3,5- methyl -6- (4- nitrobenzophenone) -1H- thiophene [2,3-D] [1,3] oxazines -2,4- diketone (compound 3)
Synthesis:
By 2- amino -4- methyl -5- (4- nitrobenzophenone)-thenoic acid (55g, 0.2mol), N made from step 2,
N'- carbonyl dimidazoles (65g, 0.4mol) and tetrahydrofuran (440ml) are added in reaction flask, are heated to 70 DEG C of reactions 2h, TLC
Monitor fully reacting.It is cooled to room temperature, 400ml ethyl acetate and 400ml tap water is added, extracts liquid separation, organic phase is successively used
1N hydrochloric acid (300ml), saturated salt solution (300ml) washing, anhydrous sodium sulfate are dry.Filtering obtains 5- methyl -6- after concentration is dry
(4- nitrobenzophenone) -1H- thiophene [2,3-D] [1,3] oxazines -2,4- diketone (compound 3) 53g, yield 87%.
Step 4,1- (2,6- difluorobenzyl) -5- methyl -6- (4- nitrobenzophenone) -1H- thiophene [2,3-D] [1,3] oxazines -
The synthesis of 2,4- diketone (compound 4):
By 5- methyl -6- (4- nitrobenzophenone) -1H- thiophene [2,3-D] [1,3] oxazines -2,4- diketone made from step 3
(30g, 0.1mol), 2,6-, bis- fluorobenzyl chloride (21.1g, 0.13mol), n,N-diisopropylethylamine (32.3g, 0.25mol) and N,
Dinethylformamide (300ml) is added in reaction flask, is heated to 100 DEG C of reactions 5h, TLC and is monitored fully reacting.It is cooled to
Room temperature, be added 1000ml tap water, with ethyl acetate (300mlX2) extract, merge organic phase, successively with 1N hydrochloric acid (200ml),
Saturated salt solution (200ml) washing, anhydrous sodium sulfate are dry.Filtering obtains crude product after concentration is dry, then uses ethanol/dichloromethane
(240ml/480ml) crystallization purifying, filtering obtain 1- (2,6- difluorobenzyl) -5- methyl -6- (4- nitrobenzophenone)-after dry
1H- thiophene [2,3-D] [1,3] oxazines -2,4- diketone (compound 4) 35g, yield 82%.
Step 5,2- ((2,6- difluorobenzyl) amino)-N- (6- methoxyl group pyridazine -3- base) -4- methyl -5- (4- nitrobenzene
Base) thiophene -3- formamide (compound 5) synthesis:
By (2,6- the difluorophenyl)-5- methyl of 1- made from step 4-6- (4- nitrobenzophenone)-1H- thiophene [2,3-D] [1,
3] oxazines -2,4- diketone (43g, 0.1mol), 3- amino -6- methoxyl group pyridazine (15g, 0.12mol), potassium carbonate (34.5g,
It 0.25mol) is added in reaction flask with n,N-Dimethylformamide (500ml), is heated to 60 DEG C of reaction 3h, TLC monitoring reactions
Completely.It is cooled to room temperature, 1500ml tap water is added, is extracted with ethyl acetate (400mlX3), merges organic phase, successively uses 1N
Hydrochloric acid (400ml), saturated salt solution (400ml) washing, anhydrous sodium sulfate are dry.Filtering obtains 2- ((2,6- bis- after concentration is dry
Luorobenzyl) amino)-N- (6- methoxyl group pyridazine -3- base) -4- methyl -5- (4- nitrobenzophenone) thiophene -3- formamide (compound
5) 48g, yield 94%.
Step 6,1- (2,6- difluorobenzyl) -3- (6- methoxyl group pyridazine -3- base) -5- methyl -6- (4- nitrobenzophenone) thiophene
The synthesis of pheno [2,3-d] pyrimidine -2,4 (1H, 3H)-diketone (compound 6):
By 2- made from step 5 ((2,6- difluorobenzyl) amino)-N- (6- methoxyl group pyridazine -3- base) -4- methyl -5-
(4- nitrobenzophenone) thiophene -3- formamide (48g, 0.094mol), N, N'- carbonyl dimidazoles (30.5g, 0.188mol) and tetrahydro
Furans (500ml) is added in reaction flask, is heated to 70 DEG C of reactions 5h, TLC and is monitored fully reacting.It is cooled to room temperature, is added
500ml ethyl acetate and 300ml tap water, extract liquid separation, and organic phase successively uses 1N hydrochloric acid (300ml), saturated salt solution
(300ml) washing, anhydrous sodium sulfate are dry.Filtering obtains crude product, then is beaten with methyl tertiary butyl ether(MTBE) (1000ml) after concentration is dry
Purifying, filtering obtain 1- (2,6- difluorobenzyl) -3- (6- methoxyl group pyridazine -3- base) -5- methyl -6- (4- nitrobenzene after dry
Base) thiophene [2,3-d] pyrimidine -2,4 (1H, 3H)-diketone (compound 6) 39g, yield 77%.
Step 7,5- (bromomethyl) -1- (2,6- difluorobenzyl) -3- (6- methoxyl group pyridazine -3- base) -6- (4- nitrobenzene
Base) synthesis of thiophene [2,3-d] pyrimidine -2,4 (1H, 3H)-diketone (compound 7):
By 1- made from step 6 (2,6- difluorobenzyl) -3- (6- methoxyl group pyridazine -3- base) -5- methyl -6- (4- nitro
Phenyl) thiophene [2,3-d] pyrimidine -2,4 (1H, 3H)-diketone (50g, 0.093mol) and carbon tetrachloride (600ml) be added to reaction
In bottle, after mixing evenly, add N- bromo-succinimide (19.9g, 0.11mol) and azodiisobutyronitrile (1.53g,
0.0093mol), heating reflux reaction 4h, TLC monitor fully reacting.It is cooled to room temperature, is washed with water (300mlX2), organic phase
It is concentrated to dryness, ethanol/dichloromethane (500ml/500ml) purifying obtains 5- (bromomethyl) -1- (2,6- difluoro benzyls after dry
Base) -3- (6- methoxyl group pyridazine -3- base) -6- (4- nitrobenzophenone) thiophene [2,3-d] pyrimidine -2,4 (1H, 3H)-diketone (chemical combination
Object 7) 48.7g, yield 85%.
Step 8,1- (2,6- difluorobenzyl) -5- ((dimethylamino) methyl) -3- (6- methoxyl group pyridazine -3- base) -6-
The synthesis of (4- nitrobenzophenone)-thiophene [2,3-d] pyrimidine -2,4 (1H, 3H)-diketone (compound 8):
By 5- made from step 7 (bromomethyl) -1- (2,6- difluorobenzyl) -3- (6- methoxyl group pyridazine -3- base) -6- (4-
Nitrobenzophenone) thiophene [2,3-d] pyrimidine -2,4 (1H, 3H)-diketone (30.8g, 0.05mol), dimethylamine hydrochloride (6.1g,
0.075mol), potassium carbonate (27.6g, 0.2mol) and n,N-Dimethylformamide (300ml) are added in reaction flask, are heated to
80 DEG C of reactions 5h, TLC monitor fully reacting.It is cooled to room temperature, 900ml tap water is added, is extracted with ethyl acetate (300mlX3)
It takes, merges organic phase, washed with saturated salt solution (300ml), anhydrous sodium sulfate is dry.Filtering obtains 1- (2,6- after concentration is dry
Difluorobenzyl) -5- ((dimethylamino) methyl) -3- (6- methoxyl group pyridazine -3- base) -6- (4- nitrobenzophenone)-thiophene [2,3-
D] pyrimidine -2,4 (1H, 3H)-diketone (compound 8) 26g, yield 90%.
Step 9,1- (2,6- difluorobenzyl) -5- ((dimethylamino) methyl) -3- (6- methoxyl group pyridazine -3- base) -6-
The synthesis of (4- aminophenyl)-thiophene [2,3-d] pyrimidine -2,4 (1H, 3H)-diketone (compound 9):
By 1- made from step 8 (2,6- difluorobenzyl) -5- ((dimethylamino) methyl) -3- (6- methoxyl group pyridazine -3-
Base) -6- (4- aminophenyl)-thiophene [2,3-d] pyrimidine -2,4 (1H, 3H)-diketone (58g, 0.1mol), 10%Pd/C (5.8g)
It is added in reaction flask with ethyl alcohol (600ml), leads to hydrogen normal temperature and pressure and react 6h, TLC monitors fully reacting.Filtering, filtrate are dense
It is reduced to 300ml, 600ml n-hexane, stirring and crystallizing 2h is added.Filtering obtains 1- (2,6- difluorobenzyl) -5- after filter cake drying
((dimethylamino) methyl) -3- (6- methoxyl group pyridazine -3- base) -6- (4- aminophenyl)-thiophene [2,3-d] pyrimidine -2,4
(1H, 3H)-diketone (compound 9) 45g, yield 82%.
The synthesis of step 10, Rui Lugeli (Relugolix):
By 1- made from step 9 (2,6- difluorobenzyl) -5- ((dimethylamino) methyl) -3- (6- methoxyl group pyridazine -3-
Base) -6- (4- aminophenyl)-thiophene [2,3-d] pyrimidine -2,4 (1H, 3H)-diketone (10g, 0.018mol), N, N'- carbonyl two
Imidazoles (5.8g, 0.036mol), n,N-diisopropylethylamine (11.6g, 0.09mol) and acetonitrile (50ml) are added to reaction flask
In, after being stirred at room temperature 30 minutes, methoxy amine hydrochlorate (7.5g, 0.09mol) is added, is heated to 50 DEG C of reactions 4.5h, TLC
Monitor fully reacting.It is cooled to room temperature, 200ml water, stirring and crystallizing 1h is added.Filtering, filter cake use ethanol/dichloromethane again
(100ml/100ml) mashing purifying, obtains Rui Lugeli (Relugolix) 8.3g, yield 74%, purity > 98% after drying.
Rui Lugeli obtained in above-described embodiment is taken, (purchase is in the poly- biological medicine of Zhejiang section with Rui Lugeli control sample
Co., Ltd) it is control, carry out nucleus magnetic hydrogen spectrum and Mass Spectrometer Method, it can be seen that Rui Lugeli and Rui Lugeli produced by the present invention
It is identical to compare spline structure, illustrates that the present invention synthesizes successfully.
1H-NMR(400MHz,CDCl3):2.16(6H,s),3.58-3.81(2H,m),3.84(3H,s),4.16(3H,
s),5.33(2H,s),6.88(2H,t),7.14(1H,d),7.22-7.68(7H,m),7.70(1H,s).
LCMS:m/z 624.0(M+H+).
To sum up, the present invention provides a kind of method for preparing Rui Lugeli, method of the invention is coupled again using first closed loop
Route, operate it is simpler, side reaction is few, and reaction condition is mild, and yield, purity is high, product purify well, be suitble to commercial size
Production.
Claims (10)
1. a kind of method for preparing Rui Lugeli midbody compound 8, it is characterised in that: the described method comprises the following steps:
(a) compound 2 and N, the reaction of N'- carbonyl dimidazoles, obtain compound 3；
(b) compound 3 and 2, bis- fluorobenzyl chloride of 6- reaction, obtains compound 4；
(c) compound 4 is reacted with 3- amino -6- methoxyl group pyridazine, obtains compound 5；
(d) compound 5 and N, the reaction of N'- carbonyl dimidazoles, obtain compound 6；
(e) compound 6 is reacted with N- bromo-succinimide, azodiisobutyronitrile, obtains compound 7；
(f) compound 7 is reacted with dimethylamine hydrochloride, obtains compound 8；
Wherein, the structure of compound 2 isThe structure of compound 3 is
The structure of compound 4 isThe structure of compound 5 isCompound
6 structure isThe structure of compound 7 isChemical combination
The structure of object 8 is
2. according to the method described in claim 1, it is characterized by: in step (a), two miaow of the compound 2 and N, N'- carbonyl
The molar ratio of azoles is 1:(1~3), reaction temperature is 60~80 DEG C, and the reaction time is 1~3h；Reaction dissolvent is organic solvent；
And/or in step (b), compound 3 and 2, the molar ratio of bis- fluorobenzyl chloride of 6- is 1:(1.0~2.0)；Reaction is in alkali
The lower progress of effect；Reaction dissolvent is organic solvent；Reaction temperature is 80~120 DEG C, and the reaction time is 3~7h；
And/or in step (c), the molar ratio of compound 4 and 3- amino -6- methoxyl group pyridazine is 1:(1~1.5)；Reaction be
It is carried out under the action of alkali；Reaction dissolvent is organic solvent；Reaction temperature is 50~70 DEG C, and the reaction time is 2~4h；
And/or in step (d), compound 5 and N, the molar ratio of N'- carbonyl dimidazoles are 1:(1~3)；Reaction dissolvent is organic
Solvent；Reaction temperature is 60~80 DEG C, and the reaction time is 3~7h；
And/or in step (e), compound 6 and N- bromo-succinimide, azodiisobutyronitrile molar ratio be 1:(1.00~
1.20): (0.08~0.20)；Reaction dissolvent is organic solvent；Reaction temperature is reflux temperature, and the reaction time is 3~5h；
And/or in step (f), the molar ratio of compound 7 and dimethylamine hydrochloride is 1:(1.0~2.0)；It is described reaction be
It is carried out in the presence of alkali；Reaction dissolvent is organic solvent；Reaction temperature is 60~100 DEG C, 3~7h of reaction time.
3. according to the method described in claim 2, it is characterized by: in step (a), two miaow of the compound 2 and N, N'- carbonyl
The molar ratio of azoles is 1:2, and reaction temperature is 70 DEG C, reaction time 2h；Reaction dissolvent is tetrahydrofuran；
And/or in step (b), compound 3 and 2, the molar ratio of bis- fluorobenzyl chloride of 6- is 1:1.3；The alkali is N, N- diisopropyl
The molar ratio of ethamine, alkali and compound 3 is 2.5:1；Reaction dissolvent is N,N-dimethylformamide；Reaction temperature is 100 DEG C, instead
It is 5h between seasonable；
And/or in step (c), the molar ratio of compound 4 and 3- amino -6- methoxyl group pyridazine is 1:1.2；The alkali is carbonic acid
The molar ratio of potassium, alkali and compound 4 is 2.5:1；Reaction dissolvent is N,N-dimethylformamide；Reaction temperature is 60 DEG C, reaction
Time is 3h；
And/or in step (d), compound 5 and N, the molar ratio of N'- carbonyl dimidazoles are 1:2；Reaction dissolvent is tetrahydrofuran；
Reaction temperature is 70 DEG C, reaction time 5h；
And/or in step (e), the molar ratio of compound 6 and N- bromo-succinimide, azodiisobutyronitrile is 1:1.08:
0.10；Reaction dissolvent is carbon tetrachloride；Reaction time is 4h；
And/or in step (f), the molar ratio of compound 7 and dimethylamine hydrochloride is 1:1.5；The alkali be potassium carbonate, alkali with
The molar ratio of compound 7 is 4:1；Reaction dissolvent is N,N-dimethylformamide；Reaction temperature is 80 DEG C, reaction time 5h.
4. according to the method described in claim 1, it is characterized by: compound 2 the preparation method comprises the following steps:
(1) 4- nitro propiophenone is reacted with ethyl cyanoacetate, sulphur powder, obtains compound 1；
(2) compound 1 is reacted with alkali, obtains compound 2；
Wherein, the structure of compound 1 is
5. according to the method described in claim 4, it is characterized by: in step (1), 4- nitro propiophenone, ethyl cyanoacetate, sulphur
The molar ratio of powder is 1:(0.8~1.2): (0.8~1.2)；The reaction carries out in the presence of alkali；The temperature of the reaction
Degree is 40~60 DEG C, and the reaction time is 4~8h, and reaction dissolvent is organic solvent；
And/or in step (2), the alkali is sodium hydroxide solution, and compound 1 and the mass volume ratio of sodium hydroxide solution are
153g:(800~1200) mL；Reaction temperature is reflux temperature, and the reaction time is 3.0~4.0h；Reaction dissolvent is organic solvent；
Preferably, in step (1), 4- nitro propiophenone, cyan-acetic ester, sulphur powder molar ratio be 1:1:1；The alkali is three
The molar ratio of ethamine, the alkali and 4- nitro propiophenone is 1:1；The temperature of the reaction is 50 DEG C, reaction time 6h；Reaction
Solvent is ethyl alcohol；
And/or in step (2), the concentration of the sodium hydroxide solution is 2mol/L, the matter of compound 1 and sodium hydroxide solution
Amount volume ratio is 153g:1000mL；Reaction temperature is reflux temperature, reaction time 3.5h；Reaction dissolvent is ethyl alcohol.
6. method according to claim 1-5, it is characterised in that: the method also includes purification steps, wherein
In step (a), method of purification are as follows: ethyl acetate and water are added in system after the reaction, extracts liquid separation, takes organic phase, successively
With the hydrochloric acid of 1mol/L, saturated common salt water washing, take organic phase, it is dry to get；
In step (b), method of purification are as follows: negate the system after answering, water is added, is extracted with ethyl acetate, takes organic phase, successively use
The hydrochloric acid of 1mol/L, saturated common salt water washing, take organic phase, obtain crude product after concentration is dry, then with volume ratio be 1:2 ethyl alcohol with
The mixed solution of methylene chloride to crude product recrystallize to get；
In step (c), method of purification are as follows: negate the system after answering, water is added, is extracted with ethyl acetate, takes organic phase, successively use
1mol/L hydrochloric acid, saturated common salt water washing, take organic phase, it is dry to get；
In step (d), method of purification are as follows: the system after answering is negated, l ethyl acetate and water is added, liquid separation is extracted, takes organic phase,
1mol/L hydrochloric acid, saturated common salt water washing are successively used, obtains crude product after taking organic phase, concentration dry, then beaten with methyl tertiary butyl ether(MTBE)
Slurry purifying, filtering, take solid to get；
In step (e), method of purification are as follows: the system after answering is negated, water is added, washs, takes organic phase, it is dry, crude product is obtained, is then used
Volume ratio be 1:1 ethyl alcohol and methylene chloride mixed solution recrystallization to get；
In step (f), method of purification are as follows: negate the system after answering, water and ethyl acetate is added, extraction takes organic phase, with saturation
Brine It, takes organic phase, it is dry to get.
7. a kind of method for preparing Rui Lugeli, it is characterised in that: the described method comprises the following steps:
(g) compound 8 made from any one of claim 1-6 the method reacts under catalyst with hydrogen, obtains compound
9；
(h) compound 9 and N, N'- carbonyl dimidazoles, methoxy amine hydrochlorate reaction, obtain Rui Lugeli；
Wherein, the structure of compound 9 isThe structure of Rui Lugeli is
8. according to the method described in claim 7, it is characterized by: the reaction is carried out in atmosphere of hydrogen in step (g)
, the mass ratio of compound 8 and catalyst is 10:(0.5~3.0), the catalyst is Pd/C；Reaction dissolvent is organic molten
Agent；Reaction temperature is room temperature, 4~8h of reaction time；
And/or in step (h), reaction process are as follows: compound 9 and N, N'- carbonyl dimidazoles first react in the presence of alkali,
Wherein, reaction temperature is room temperature, and the reaction time is 30 minutes；Then reaction system is added in methoxy amine hydrochlorate again, continued
Reaction, wherein reaction temperature is 50 DEG C, reaction time 4.5h.
9. according to the method described in claim 8, it is characterized by: in step (g), compound 8 and the mass ratio of catalyst are
10:1.0, the catalyst are 10%Pd/C；Reaction dissolvent is ethyl alcohol；Reaction time 6h；
And/or in step (h), compound 9 and N, N'- carbonyl dimidazoles, methoxy amine hydrochlorate molar ratio be 1:2:5, institute
Alkali is stated as n,N-diisopropylethylamine, the molar ratio of alkali and compound 9 is 1:2；Reaction dissolvent is acetonitrile.
10. according to the described in any item methods of claim 7-9, it is characterised in that: the method also includes purification step,
In, in step (g), method of purification are as follows: negate the system after answering, filter, filtrate is taken to be concentrated, be added after concentration 2 times of liquid volume
N-hexane, stirring and crystallizing 2h, filtering, take solid to get；
In step (h), method of purification are as follows: negate the system after answering, water, stirring and crystallizing 1h is added, filtering takes solid, then use body
Product than be 1:1 ethyl alcohol and methylene chloride mixed solution be beaten purifying, filtering, take solid to get.
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