CN107954990A - A kind of preparation method of Lei Dipawei - Google Patents
A kind of preparation method of Lei Dipawei Download PDFInfo
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- CN107954990A CN107954990A CN201711120493.2A CN201711120493A CN107954990A CN 107954990 A CN107954990 A CN 107954990A CN 201711120493 A CN201711120493 A CN 201711120493A CN 107954990 A CN107954990 A CN 107954990A
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- 0 C=C(C*1)C[C@]1C(O)=O Chemical compound C=C(C*1)C[C@]1C(O)=O 0.000 description 8
- DKSYLEFLMUQPDJ-UHFFFAOYSA-N FC1(c(cc(cc2)I)c2-c(cc2)c1cc2Br)F Chemical compound FC1(c(cc(cc2)I)c2-c(cc2)c1cc2Br)F DKSYLEFLMUQPDJ-UHFFFAOYSA-N 0.000 description 2
- GWUPMAMGLLLLHO-UHFFFAOYSA-N Brc(cc1)cc(Cc2c3)c1-c2ccc3I Chemical compound Brc(cc1)cc(Cc2c3)c1-c2ccc3I GWUPMAMGLLLLHO-UHFFFAOYSA-N 0.000 description 1
- FXSCJZNMWILAJO-UHFFFAOYSA-N Brc(cc1C2)ccc1-c1c2cccc1 Chemical compound Brc(cc1C2)ccc1-c1c2cccc1 FXSCJZNMWILAJO-UHFFFAOYSA-N 0.000 description 1
- DTXOERCSHGWJJL-UHFFFAOYSA-N C=[Br]c(cc1C2)ccc1-c(cc1)c2cc1I Chemical compound C=[Br]c(cc1C2)ccc1-c(cc1)c2cc1I DTXOERCSHGWJJL-UHFFFAOYSA-N 0.000 description 1
- KHQZXVZXRCFXSC-UHFFFAOYSA-N O=C(CCl)c(cc1)cc(C(c2c3)(F)F)c1-c2ccc3Br Chemical compound O=C(CCl)c(cc1)cc(C(c2c3)(F)F)c1-c2ccc3Br KHQZXVZXRCFXSC-UHFFFAOYSA-N 0.000 description 1
- DJALQTLGSDTQNA-ZCFIWIBFSA-N OC([C@H]1CNCC2(CC2)C1)=O Chemical compound OC([C@H]1CNCC2(CC2)C1)=O DJALQTLGSDTQNA-ZCFIWIBFSA-N 0.000 description 1
- PHAZHDFGWRCTFR-LURJTMIESA-N OC([C@H]1NCC2(CC2)CC1)=O Chemical compound OC([C@H]1NCC2(CC2)CC1)=O PHAZHDFGWRCTFR-LURJTMIESA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a kind of preparation method of Lei Dipawei, include the following steps：(1) preparation of 1 LD B of Lei Dipawei intermediate products, (2) preparation of 2 LD E of Lei Dipawei intermediate products, (3) preparation of 3 LD F of Lei Dipawei intermediate products, (4) preparation of 4 LD J of Lei Dipawei intermediate products, (5) preparation of 5 LD L of Lei Dipawei intermediate products, the preparation of (6) Lei Dipawei LD Q.The advantage of the invention is that：Technical maturity is stablized, and product quality is stablized, and production technology is safe and reliable, is adapted to industrialized production.
Description
Technical field
The present invention relates to bulk pharmaceutical chemicals and intermediate preparing technical field, more particularly to a kind of preparation method of Lei Dipawei.
Background technology
Lei Dipawei (also known as Suo Feibuwei) is mainly used for treating hepatitis C infection.Viral hepatitis type C referred to as the third type
Hepatitis or hepatitis, are a kind of virus hepatitis as caused by Hepatitis C Virus (HCV) infection.According to the statistics of the World Health Organization,
The infection rate of global HCV is about 3%, altogether about 1.8 hundred million people.Hepatitis patient about 3,200,000 people in the U.S..HCV infection is mainly wrapped
Immune-mediated and two kinds of HCV coup injuries are included, cause liver inflammation after infection so that liver function declines even exhaustion, pathology table
Now based on necrosis of liver cells and lymphocytic infiltration.Hepatic injury disease is for a long time just found after most hepatitis patient infection
Shape.It is hepatic sclerosis that infection, which has 10%~20% patient evolution for 20 to 30 years, and 1%-5% patient can be because occurring hepatocellular carcinoma
(HCC) it is dead.And decompensation situation once occurs in hepatic sclerosis, such as there is jaundice, seroperitoneum, variceal bleeding,
Hepatic encephalopathy etc., its survival rate can drastically decline.
Harvoni is the anti-hepatitis hit product Sovaldi (common names of lucky moral：Sofosbuvir Suo Feibuwei) and it is fixed
The compound combination of the protease N S5A inhibitor ledipasvir of dosage.Harvoni is that first approval is used for 1 type of therapeutic gene
Hepatitis C infections, and the entirely oral anti-hepatitis scheme of interferon or Ribavirin need not be combined.Harvoni both can single medicine make
With, can also with other oral formulations such as ribavirin combination use.
The critical data of FDA approvals Harvoni is supported to share the 3 phases clinic of 1518 patients' participations essentially from 3 in fact
Test.These patients did not received treatment before having, and received treatment before also including but unsatisfactory curative effect and contained hepatic sclerosis
Patient.Subject be randomly divided into Harvoni single therapies group or with ribavirin combination medication group.Level-one observation terminal is to control
Continued viral response rate (SVR12) after treating 12 weeks.It turns out that the experiment of first 3 phase have 94% before do not received to control
The patient for the treatment of treatment 8 weeks after obtain continued viral response, and the course for the treatment of extend to 12 weeks after continued viral response rate increasing
Add to 96%.Second 3 phases clinical trial containing part liver cirrhosis patient obtains 99% continued viral after treating 12 weeks
Learn response rate.Received to treat before 3rd clinical trial evaluation but there is no response, and the patient including some hepatic sclerosis.
The patient for having 94% and 99% respectively by the Harvoni treatments of 12 and 24 weeks obtains continued viral response.In these experiments
Common side effect is fatigue and headache.
The content of the invention
It is proposed in the above background technology to solve it is an object of the invention to provide a kind of preparation method of Lei Dipawei
Problem.
To achieve the above object, the present invention provides following technical solution：A kind of preparation method of Lei Dipawei is provided, is wrapped
Include：
Step (1)：The preparation of Lei Dipawei intermediate products 1-LD-B：
(A1) preparation of LD-A
(A2) preparation of LD-B
Step (2)：The preparation of Lei Dipawei intermediate products 2-LD-E：
(A1) preparation of LD-C
(A2) prepared by LD-D
(A3) prepared by LD-E
Step (3)：The preparation of Lei Dipawei intermediate products 3-LD-F：
Step (4)：The preparation of Lei Dipawei intermediate products 4-LD-J：
(A1) prepared by LD-G
(A2) prepared by LD-H
(A3) prepared by LD-I
(A4) preparation of grignard reagent
(A5) prepared by LD-J
Step (5)：The preparation of Lei Dipawei intermediate products 5-LD-L：
(A1) prepared by LD-K
(A2) prepared by LD-L
Step (6)：The preparation of bulk pharmaceutical chemicals Lei Dipawei-LD-Q：
(A1) prepared by LD-O
(A2) prepared by LD-P
(A3) prepared by LD-Q
One of preferred embodiment as the present invention, step (1) concretely comprises the following steps：
A1. 19-21% sodium hydrate aqueous solutions, tetrahydrofuran and LD-SM1 are added into reaction kettle, stirs dissolved clarification, control
20-30 DEG C, the tetrahydrofuran solution of the acid anhydrides containing BOC is slowly dropped into reaction kettle, drips off 20-30 DEG C of reaction 4-5h of insulation,
The reaction was complete for control in HPLC, is layered organic phase saturated common salt water washing, is concentrated under reduced pressure, and obtains grease LD-A and throws in next step；
A2. LD-A is added in reaction kettle, dichloromethane, is cooled to 0-2 DEG C, adds tetramethyl piperidine nitrogen oxides, then
Liquor natrii hypochloritis is slowly added into, while (HPLC monitorings) is completed in 0-5 DEG C of stirring to reaction, then adds the sulfuric acid of 8-12%
Potassium solution, stirs 0.3-0.8h, layering, and organic phase is washed with the salt of 4-6% sodium thiosulfate solutions and 12-18%, decompression
Concentration, residue add petroleum ether, are maintained at 10-20 DEG C of stirring 1-3h, and filtration drying obtains solid LD-B.
One of preferred embodiment as the present invention, step (2) concretely comprise the following steps：
A1. Diethylaminoethyl triphen phosphonium salt, 2- methyltetrahydrofurans, solid potassium tert-butoxide are put into reaction kettle, and is protected
Temperature is held at 0-2 DEG C, when 15-25 DEG C of stirring 1-3 is small (holding suspension), is cooled to 0-2 DEG C, under conditions of less than 6 DEG C,
Add LD-B, then reaction solution warm naturally to room temperature and stir 7-9 it is small when, be cooled to 0-2 DEG C, add 6-8% sodium acid carbonates molten
Liquid stopped reaction, separates water layer, and organic layer is extracted with 7% sodium bicarbonate solution, and the water layer of merging is filtered through diatomite, by water
Layer is acidified below 10 DEG C with 6M hydrochloric acid, is extracted 2 times with isopropyl acetate, is concentrated under reduced pressure into 400L, adds petroleum ether, 20-30
DEG C stirring 1-2 it is small when, filtration drying obtains solid LD-C；
A2. compound L D-C, benzyltrimethylammonium chloride, bromofom and dichloromethane are added in reaction kettle, adds 48-
52% sodium hydroxide solution (control temperature is no more than 38 DEG C), when 28-32 DEG C of stirring 1-3 is small, HPLC monitoring reactions are completed, cold
But to 18-22 DEG C, water is added, stands 1-3h, branch vibration layer, and with 1M salt acid elution organic layers, be then washed with water organic
Layer, is concentrated under reduced pressure into 380-420L, adds petroleum ether and is cooled to 18-22 DEG C, stirs 2h at 18-20 DEG C, filter, use petroleum ether
Filter cake is washed, the drying at 38-42 DEG C, obtains the LD-D of solid by product；
A3. compound L D-D is added into reaction kettle, isopropanol, is then heated to 38-42 DEG C by reaction solution, by hydroxide
Potassium is added in solution, and is stirred until solid dissolves, and with nitrogen displacement 3 times, is then added 8-12% palladium carbons, is replaced with hydrogen
1 time, and 2-5 atmospheric pressure hydrogenation is kept at 38-42 DEG C, analyzed by HPLC and determine that reaction is completed, reaction is finished, and solution is cooled down
To 20-22 DEG C, and with nitrogen displacement 3 times, reacting liquid filtering is removed into solid, with water wash solid, is then concentrated solution
To the half of its initial volume, methylate tertbutyl ether and 4N hydrochloric acid extracting and demixings, water layer are extracted with methyl tertiary butyl ether(MTBE), are merged
Organic phase, is washed with water, and solution decompression is concentrated into 480-520L, adds petroleum ether, is cooled to 10-20 DEG C, stirs 1-3h, mistake
Solid LD-E is dried to obtain in filter.
One of preferred embodiment as the present invention, step (3) concretely comprise the following steps：
LD-E is added into reaction kettle, tetrahydrofuran, is then heated to 30-35 DEG C by solution, is slowly added to contain the tert-butyl alcohol
The tetrahydrofuran solution of potassium so that internal temperature is no more than 40 DEG C, reaction solution is stirred 25-30 minutes, then slow cooling is extremely
18-22 DEG C, continue to stir 0.5-1.5h at 18-22 DEG C, filter, filter cake is washed with tetrahydrofuran, by solid at 38-42 DEG C
In vacuum drying 22-26h, solid LD-F is obtained.
One of preferred embodiment as the present invention, step (4) concretely comprise the following steps：
A1. LD-SM2,1-methyl-2-pyrrolidinone are added into reaction kettle, stirring adds bromide reagent in batches to dissolving
N- bromo-succinimides, then add catalyst benzoyl peroxide, and controlling reaction temperature is at 60-70 DEG C, stirring reaction 7-9
Hour, HPLC monitoring reactions are completed, and are cooled to 18-22 DEG C, add water, layering, lower floor's liquid, which adds methanol, has a large amount of solids to analyse
Go out, white solid LD-G is dried to obtain in centrifugation；
A2. LD-G and acetic acid are added in reaction kettle, is heated to 40-45 DEG C, and stirred 25-35 minutes, dissolved clarification, adjusted
Temperature of reaction kettle adds 18-22% sulfuric acid to after 20-30 DEG C, is subsequently added into iodine, Potassiumiodate, by reaction solution at 56-60 DEG C plus
Hot 3.5-4.5h, HPLC monitoring reaction are completed, and reaction solution then are cooled to 20-25 DEG C, by the sodium sulfite solution of 8-10%
Add in reaction mixture, maintain the temperature at 20-30 DEG C, continue to stir 0.5-1.5h, centrifugation, filter cake water wash is dry, obtains
To solid product LD-H；
A3. tetrahydrofuran, LD-H, N- fluorobenzenesulfonimide (NFSI) will be added in reaction kettle, stirring makes solid molten
Solution, nitrogen displacement 3 times, under nitrogen protection, is cooled to -75- (- 65) DEG C, temperature is maintained at less than less than -55 DEG C by reaction solution
The hexane solution (1.0M) of butyl lithium is added dropwise, drop finishes, -60 DEG C of internal temperature of control is following, and the reaction was continued 1.5-2h (HPLC prisons
Reaction is controlled to complete), add methanol and reaction is quenched, after adjusting extremely -22- (- 18) DEG C of temperature, HPLC is analysis shows that go out excessive N-
Oxo benzene carbimide completely consumes, and by temperature adjustment to 0-2 DEG C, adds n-hexane, continues stirring 20-30 minutes, filter, uses
N-hexane elutes filter cake, and filtrate is concentrated in vacuo to 2.5-3.0 volumes below 28 DEG C, dichloromethane is added, is heated to reflux 40-
60 minutes, mixture is concentrated into 3.5-4.5 volumes, adds other methanol, and solution is again concentrated to 3.5-4.5 bodies
Product, cools down, filtering, and with methanol elution twice, it is dry, obtain the product LD-I of solid.
A4. tetrahydrofuran is added into reaction kettle, magnesium chips is heated to 45-55 DEG C, after temperature stabilization, adds containing THF and different
The solution of propyl chloride, continues stirring to there is obvious heating；Continue that the mixed liquor containing THF and isopropyl chloride is added dropwise, drop finishes, after continuation of insurance
Warm 45-55 DEG C of stirring 3-4h, the direct barrelling of the solution is in next step after cooling；
A5. LD-I and tetrahydrofuran will be added in reaction kettle；Nitrogen displacement 3 times, under nitrogen protection, solution is cooled down
Extremely -12- (- 8) DEG C, is slowly added to the THF solution of 2N isopropylmagnesium chlorides, and gained reaction solution stirs 1- at -12- (- 8) DEG C
2h, until the reaction is complete, the chloro- N- methoxy N-methylacetamides of 2- are dissolved in methyl tertiary butyl ether(MTBE), then will
The chloro- N- methoxy N-methylacetamides solution of 2- is slowly added in reaction kettle, and internal temperature is kept during dropwise addition at -10 DEG C
To 0 DEG C, drop finishes, and internal temperature is adjusted to 0-2 DEG C, continues to stir 2h, after the completion of reaction, adds 1N hydrochloric acid, layering, and use first
Base tertbutyl ether aqueous layer extracted, merges organic layer, is concentrated under reduced pressure into 10 volumes, and adjustment temperature stirs 1.5- to 20-25 DEG C
2.5h, centrifugation, and filter cake is washed with isopropanol, and it is dry, obtain the product LD-J of solid.
One of preferred embodiment as the present invention, step (5) concretely comprise the following steps：
A1. compound L D-J and compound L D-F, acetone are added in reaction kettle, is heated to 50-60 DEG C, and stir
1.5-2.5h to HPLC measure reactions are completed, and are slowly added to water, and solution is kept for 25-35 minutes at 50-60 DEG C, are cooled to
15-25 DEG C, centrifugation, and filter cake is washed with water, and it is dry, obtain solid LD-K；
A2. compound L D-K, ammonium acetate, toluene and 2-methyl cellosolve are added into reaction kettle, is heated the mixture to
85-95 DEG C, and complete (HPLC monitorings) to reaction within 7-9 hours in 85-95 DEG C of stirring, solution is cooled to 50-60 DEG C, stirring is extremely
Solid is separated out, normal heptane is added at 50-60 DEG C, material is then cooled to 20-22 DEG C in 2.5-3.5h, continues to stir
0.5-1.5h, filtering, and washed with normal heptane, solid LD-L is dried to obtain at 40-50 DEG C.
One of preferred embodiment as the present invention, step (6) concretely comprise the following steps：
A1. compound L D-M, double (pinacol) two boron, potassium propionate and tert-butyl diphenyl phosphine palladium bichloride are added into reaction kettle
In, nitrogen displacement 3 times, adds isopropyl acetate, reaction mixture is heated to 70-80 DEG C, and stirs 3-4h, is cooled to
After 20-30 DEG C, compound L D-L is added in reaction mixture, nitrogen displacement, the 1M potassium phosphate solutions of degassing are added into reaction
In device, and reaction mixture is heated to 70-80 DEG C, continues to stir 0.5-1.5h, be subsequently cooled to 35-40 DEG C, add N-
Acetyl-L-cysteine, continues to stir 0.5-1.5h, and reaction mixture is cooled to 18-22 DEG C, stops stirring, stands and divides
From, water phase is separated, and N-acetyl-L-cysteine is added in organic layer, reaction mixture is heated to 45-50 DEG C,
Mixture is stirred into 1.5-2.5h at 45-50 DEG C, is cooled to 18-22 DEG C, and adds the sodium hydroxide solution of 4-6%, point
Organic layer is washed from water phase, and with 4-6% sodium chloride solutions, is concentrated under reduced pressure, adds isopropyl acetate afterwards, be heated to 45-
55 DEG C, then by containing oxalic acid ethanol solution add mixture in, and at 45-55 DEG C stir 7-9 it is small when, filtering, and
40-50 DEG C of drying under vacuo, obtains the LD-O of solid；
A2. acetonitrile, LD-O are added into reaction kettle, 1.2N hydrochloric acid is added, reaction mixture is stirred at 60-70 DEG C
The temperature of reaction mixture is adjusted to 40-50 DEG C by 1.5-2.5h to completion (HPLC monitoring) is reacted, and continues to stir 0.5-1.5h,
18-22 DEG C is cooled to, is filtered, it is dry, obtain solid LD-P；
A3. by 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate, I-hydroxybenzotriazole, N- (methoxies
Carbonyl)-Valine and n,N-Dimethylformamide added in reaction kettle, reaction mixture is stirred into 0.5- at 20-26 DEG C
1.5 it is small when, solution is then cooled to 0-2 DEG C, LD-P and N-methylmorpholine are added in reaction kettle, warm naturally to room temperature,
And continue to stir 3.5-4.5h, add ethyl acetate and water, be layered, organic phase 4-6% sodium acid carbonates and water washing, then
Organic layer is distilled to 2-3 volumes, is cooled to 20-26 DEG C, acetone is added in reaction kettle, continues to stir 2.5-3.5h, centrifuges,
Filter cake is washed with acetone, dry, obtains solid LD-Q.
Compared with prior art, the beneficial effects of the invention are as follows：Technical maturity is stablized, and product quality is stablized, production technology
Securely and reliably, it is adapted to industrialized production.
Embodiment
Technical scheme is described in more detail with reference to embodiment.
Embodiment 1
A kind of preparation method of Lei Dipawei, includes the following steps：
Step (1)：The preparation of Lei Dipawei intermediate products 1-LD-B：
(A1) preparation of LD-A
Synthesis flow：
Preparation process：19% sodium hydrate aqueous solution, tetrahydrofuran and LD-SM1 are added into reaction kettle, stirs dissolved clarification,
20 DEG C of control, the tetrahydrofuran solution of the acid anhydrides containing BOC is slowly dropped into reaction kettle, is dripped off in insulation 20 DEG C of reactions 4h, HPLC
The reaction was complete for control, is layered organic phase saturated common salt water washing, is concentrated under reduced pressure, and obtains grease LD-A and throws in next step；
(A2) preparation of LD-B
Synthesis flow：
Preparation process：LD-A is added in reaction kettle, dichloromethane, is cooled to 0 DEG C, adds tetramethyl piperidine nitrogen oxides,
Then liquor natrii hypochloritis is slowly added into, while (HPLC monitorings) is completed in 0 DEG C of stirring to reaction, then adds 8% sulfuric acid
Potassium solution, stirs 0.3h, layering, and organic phase is washed with 4% sodium thiosulfate solution and 12% salt, is concentrated under reduced pressure, and is remained
Thing adds petroleum ether, is maintained at 10 DEG C of stirring 1h, and filtration drying obtains solid LD-B.
Step (2)：The preparation of Lei Dipawei intermediate products 2-LD-E：
(A1) preparation of LD-C
Synthesis flow：
Preparation process：Diethylaminoethyl triphen phosphonium salt, 2- methyltetrahydrofurans, solid t-butyl alcohol are put into reaction kettle
Potassium, and 0 DEG C is maintained the temperature at, when 15 DEG C of stirrings 1 are small (holding suspension), 0 DEG C is cooled to, under conditions of 0 DEG C, is added
LD-B, when then reaction solution warms naturally to room temperature and small stirring 7, is cooled to 0 DEG C, adds 6% sodium bicarbonate solution stopped reaction,
Water layer is separated, 7% sodium bicarbonate solution extraction of organic layer, the water layer of merging filters through diatomite, by water layer at 0 DEG C with 6M
Hydrochloric acid is acidified, and is extracted 2 times with isopropyl acetate, is concentrated under reduced pressure into 400L, adds petroleum ether, when 20 DEG C of stirrings 1 are small, filtration drying
Obtain solid LD-C；
(A2) prepared by LD-D
Synthesis flow：
Preparation process：By compound L D-C, benzyltrimethylammonium chloride, bromofom and dichloromethane are added in reaction kettle, are added
Enter 48% sodium hydroxide solution (control temperature is no more than 38 DEG C), when 28 DEG C of stirrings 1 are small, HPLC monitoring reactions are completed, cooling
To 18 DEG C, add water, stand 1h, branch vibration layer, and use 1M salt acid elution organic layers, organic layer is then washed with water, decompression
380L is concentrated into, petroleum ether is added and is cooled to 18 DEG C, stir 2h at 18 DEG C, filter, with petroleum ether filter cake, product is existed
It is dry at 38 DEG C, obtain the LD-D of solid；
(A3) prepared by LD-E
Synthesis flow：
Preparation process：Compound L D-D is added into reaction kettle, isopropanol, is then heated to 38 DEG C by reaction solution, by hydrogen
Potassium oxide is added in solution, and is stirred until solid dissolves, and with nitrogen displacement 3 times, is then added 8% palladium carbon, is put with hydrogen
Change 1 time, and 2 atmospheric pressure hydrogenations are kept at 38 DEG C, analyzed by HPLC and determine that reaction is completed, reaction is finished, and solution is cooled to
20 DEG C, and with nitrogen displacement 3 times, reacting liquid filtering is removed into solid, with water wash solid, at the beginning of solution then is concentrated into it
The half of initial body product, methylate tertbutyl ether and 4N hydrochloric acid extracting and demixings, water layer are extracted with methyl tertiary butyl ether(MTBE), are merged organic
Phase, is washed with water, and solution decompression is concentrated into 480L, adds petroleum ether, is cooled to 10 DEG C, stirs 1h, filtering drying obtains solid
LD-E。
Step (3)：The preparation of Lei Dipawei intermediate products 3-LD-F：
Synthesis flow：
Preparation process：LD-E is added into reaction kettle, tetrahydrofuran, is then heated to 30 DEG C by solution, is slowly added to contain
The tetrahydrofuran solution of potassium tert-butoxide so that 30 DEG C of internal temperature, reaction solution is stirred 25 minutes, then slow cooling to 18
DEG C, continue to stir 0.5h at 18 DEG C, filter, filter cake is washed with tetrahydrofuran, solid is being dried in vacuo 22h at 38 DEG C,
Obtain solid LD-F.
Step (4)：The preparation of Lei Dipawei intermediate products 4-LD-J：
(A1) prepared by LD-G
Synthesis flow：
Preparation process：LD-SM2,1-methyl-2-pyrrolidinone are added into reaction kettle, stirring adds bromine in batches to dissolving
Change reagent N-bromo-succinimide, then add catalyst benzoyl peroxide, controlling reaction temperature is at 60 DEG C, stirring reaction
7 it is small when, HPLC monitoring reactions are completed, and are cooled to 18 DEG C, add water, and layering, lower floor's liquid, which adds methanol, has a large amount of solids to separate out,
White solid LD-G is dried to obtain in centrifugation；
(A2) prepared by LD-H
Synthesis flow：
Preparation process：LD-G and acetic acid are added in reaction kettle, are heated to 40 DEG C, and is stirred 25 minutes, dissolved clarification, is adjusted
Temperature of reaction kettle adds 18% sulfuric acid, is subsequently added into iodine to after 20 DEG C, and Potassiumiodate, 3.5h is heated by reaction solution at 56 DEG C,
HPLC monitoring reactions are completed, and reaction solution then is cooled to 20 DEG C, 8% sodium sulfite solution is added in reaction mixture,
20 DEG C are maintained the temperature at, continues to stir 0.5h, centrifugation, filter cake water wash is dry, obtains solid product LD-H；
(A3) prepared by LD-I
Synthesis flow：
Preparation process：Tetrahydrofuran, LD-H, N- fluorobenzenesulfonimide (NFSI) will be added in reaction kettle, stirring makes solid
Body dissolves, nitrogen displacement 3 times, under nitrogen protection, reaction solution is cooled to -75 DEG C, temperature keeps less than -60 DEG C dropwise addition butyl
The hexane solution (1.0M) of lithium, drips and finishes, and controls -60 DEG C of internal temperature, and 1.5 (HPLC monitoring reactions completions) that the reaction was continued, add
Enter methanol and reaction is quenched, after adjusting extremely -22 DEG C of temperature, HPLC disappears completely analysis shows that going out excessive N- oxo benzene carbimides
Consumption, by temperature adjustment to 0 DEG C, adds n-hexane, continues stirring 20 minutes, filtering, elutes filter cake, by filtrate 20 with n-hexane
2.5 volumes are concentrated in vacuo to below DEG C, dichloromethane is added, is heated to reflux 40 minutes, mixture is concentrated into 3.5 volumes, is added
Enter other methanol, and solution is again concentrated to 3.5 volumes, cools down, filtering, and with methanol elution twice, it is dry, obtain
The product LD-I of solid.
(A4) preparation of grignard reagent
Synthesis flow：
Preparation process：Tetrahydrofuran is added into reaction kettle, magnesium chips, is heated to 45 DEG C, after temperature stabilization, addition contains THF
With the solution of isopropyl chloride, continue stirring to there is obvious heating；Continuing that the mixed liquor containing THF and isopropyl chloride is added dropwise, drop finishes, after
45 DEG C of stirring 3h of continuation of insurance temperature, the direct barrelling of the solution is in next step after cooling；
(A5) prepared by LD-J
Synthesis flow：
Preparation process：LD-I and tetrahydrofuran will be added in reaction kettle；Nitrogen displacement 3 times, under nitrogen protection, by solution
- 12 DEG C are cooled to, is slowly added to the THF solution of 2N isopropylmagnesium chlorides, gained reaction solution stirs 1h at -12 DEG C, until anti-
Should be complete, the chloro- N- methoxy N-methylacetamides of 2- are dissolved in methyl tertiary butyl ether(MTBE), then by the chloro- N- of 2-
Methoxy N-methylacetamide solution is slowly added in reaction kettle, and internal temperature is kept during dropwise addition, and at -10 DEG C, drop finishes, will in
Portion's temperature is adjusted to 0 DEG C, continues to stir 2h, after the completion of reaction, adds 1N hydrochloric acid, layering, and with methyl tertiary butyl ether(MTBE) extraction water
Layer, merges organic layer, is concentrated under reduced pressure into 10 volumes, and adjustment temperature stirs 1.5h to 20 DEG C, centrifuges, and use isopropanol
Filter cake is washed, it is dry, obtain the product LD-J of solid.
Step (5)：The preparation of Lei Dipawei intermediate products 5-LD-L：
(A1) prepared by LD-K
Synthesis flow：
Preparation process：By compound L D-J and compound L D-F, acetone is added in reaction kettle, is heated to 50 DEG C, and stir
Mix 1.5h to HPLC measure reactions to complete, be slowly added to water, and solution is kept for 25 minutes at 50 DEG C, be cooled to 15 DEG C, from
The heart, and filter cake is washed with water, it is dry, obtain solid LD-K；
(A2) prepared by LD-L
Synthesis flow：
Preparation process：Compound L D-K, ammonium acetate, toluene and 2-methyl cellosolve are added into reaction kettle, by mixture
85 DEG C are heated to, and (HPLC monitorings) is completed in 85 DEG C of stirrings extremely reaction in 7 hours, solution is cooled to 50 DEG C, stirring to precipitation
Solid, adds normal heptane at 50 DEG C, then material is cooled to 20 DEG C in 2.5h, continues to stir 0.5h, filters, and with just
Heptane wash, is dried to obtain solid LD-L at 40 DEG C.
Step (6)：The preparation of bulk pharmaceutical chemicals Lei Dipawei-LD-Q：
(A1) prepared by LD-O
Synthesis flow：
Preparation process：Compound L D-M, double (pinacol) two boron, potassium propionate and tert-butyl diphenyl phosphine palladium bichloride are added
In reaction kettle, nitrogen displacement 3 times, adds isopropyl acetate, reaction mixture is heated to 70 DEG C, and stirs 3h, is cooled to
After 20 DEG C, compound L D-L is added in reaction mixture, nitrogen displacement, the 1M potassium phosphate solutions of degassing are added into reactor
In, and reaction mixture is heated to 70 DEG C, continue to stir 0.5h, be subsequently cooled to 35 DEG C, add N- acetyl-L- half
Cystine, continues to stir 0.5h, and reaction mixture is cooled to 18 DEG C, stops stirring, standing separation, separates water phase, and will
N-acetyl-L-cysteine is added in organic layer, and reaction mixture is heated to 45 DEG C, mixture is stirred at 45 DEG C
1.5h, is cooled to 18 DEG C, and adds 4% sodium hydroxide solution, separates water phase, and washed with 4% sodium chloride solution
Machine layer, is concentrated under reduced pressure, and adds isopropyl acetate afterwards, is heated to 45 DEG C, and the ethanol solution containing oxalic acid then is added mixture
In, and when stirring 7 is small at 45 DEG C, filtering, and 40 DEG C of dryings under vacuo obtain the LD-O of solid；
(A2) prepared by LD-P
Preparation process：Acetonitrile, LD-O are added into reaction kettle, 1.2N hydrochloric acid is added, by reaction mixture at 60 DEG C
The temperature of reaction mixture is adjusted to 40 DEG C by stirring 1.5h to completion (HPLC monitoring) is reacted, and is continued to stir 0.5h, is cooled to 18
DEG C, filter, it is dry, obtain solid LD-P；
(A3) prepared by LD-Q
Preparation process：By 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate, I-hydroxybenzotriazole,
N- (methoxycarbonyl group)-Valine and n,N-Dimethylformamide are added in reaction kettle, and reaction mixture is stirred at 20 DEG C
0.5 it is small when, solution is then cooled to 0 DEG C, LD-P and N-methylmorpholine are added in reaction kettle, warm naturally to room temperature, and
And continue to stir 3.5h, add ethyl acetate and water, layering, organic phase 4% sodium acid carbonate and water washing, then by organic layer
Distillation is cooled to 20 DEG C, acetone is added in reaction kettle, continue to stir 2.5h, centrifugation, filter cake is washed with acetone, is done to 2 volumes
It is dry, obtain solid LD-Q.
Embodiment 2
A kind of preparation method of Lei Dipawei, includes the following steps：
Step (1)：The preparation of Lei Dipawei intermediate products 1-LD-B：
(A1) preparation of LD-A
Synthesis flow：
Preparation process：20% sodium hydrate aqueous solution, tetrahydrofuran and LD-SM1 are added into reaction kettle, stirs dissolved clarification,
25 DEG C of control, the tetrahydrofuran solution of the acid anhydrides containing BOC is slowly dropped into reaction kettle, drips off insulation 25 DEG C of reactions 4.5h, HPLC
The reaction was complete for middle control, is layered organic phase saturated common salt water washing, is concentrated under reduced pressure, and obtains grease LD-A and throws in next step；
(A2) preparation of LD-B
Synthesis flow：
Preparation process：LD-A is added in reaction kettle, dichloromethane, is cooled to 1 DEG C, adds tetramethyl piperidine nitrogen oxides,
Then liquor natrii hypochloritis is slowly added into, while (HPLC monitorings) is completed in 3 DEG C of stirrings to reaction, then adds 10% sulfuric acid
Potassium solution, stirs 0.5h, layering, and organic phase is washed with 5% sodium thiosulfate solution and 15% salt, is concentrated under reduced pressure, and is remained
Thing adds petroleum ether, is maintained at 15 DEG C of stirring 2h, and filtration drying obtains solid LD-B.
Step (2)：The preparation of Lei Dipawei intermediate products 2-LD-E：
(A1) preparation of LD-C
Synthesis flow：
Preparation process：Diethylaminoethyl triphen phosphonium salt, 2- methyltetrahydrofurans, solid t-butyl alcohol are put into reaction kettle
Potassium, and 1 DEG C is maintained the temperature at, when 20 DEG C of stirrings 2 are small (holding suspension), 1 DEG C is cooled to, under conditions of 3 DEG C, is added
LD-B, when then reaction solution warms naturally to room temperature and small stirring 8, is cooled to 1 DEG C, adds 7% sodium bicarbonate solution stopped reaction,
Water layer is separated, 8% sodium bicarbonate solution extraction of organic layer, the water layer of merging filters through diatomite, by water layer at 5 DEG C with 6M
Hydrochloric acid is acidified, and is extracted 2 times with isopropyl acetate, is concentrated under reduced pressure into 400L, is added petroleum ether, when 25 DEG C of stirrings 1.5 are small, crossed and be filtered dry
It is dry to obtain solid LD-C；
(A2) prepared by LD-D
Synthesis flow：
Preparation process：By compound L D-C, benzyltrimethylammonium chloride, bromofom and dichloromethane are added in reaction kettle, are added
Enter 50% sodium hydroxide solution (35 DEG C of temperature of control), when 30 DEG C of stirring 1-3 are small, HPLC monitoring reactions are completed, and are cooled to 20
DEG C, water is added, stands 2h, branch vibration layer, and with 1M salt acid elution organic layers, organic layer is then washed with water, is concentrated under reduced pressure
To 400L, add petroleum ether and be simultaneously cooled to 20 DEG C, stir 2.5h at 19 DEG C, filtering, with petroleum ether filter cake, by product 40
It is dry at DEG C, obtain the LD-D of solid；
(A3) prepared by LD-E
Synthesis flow：
Preparation process：Compound L D-D is added into reaction kettle, isopropanol, is then heated to 40 DEG C by reaction solution, by hydrogen
Potassium oxide is added in solution, and is stirred until solid dissolves, and with nitrogen displacement 3 times, is then added 10% palladium carbon, is put with hydrogen
Change 1 time, and 3 atmospheric pressure hydrogenations are kept at 40 DEG C, analyzed by HPLC and determine that reaction is completed, reaction is finished, and solution is cooled to
21 DEG C, and with nitrogen displacement 3 times, reacting liquid filtering is removed into solid, with water wash solid, at the beginning of solution then is concentrated into it
The half of initial body product, methylate tertbutyl ether and 4N hydrochloric acid extracting and demixings, water layer are extracted with methyl tertiary butyl ether(MTBE), are merged organic
Phase, is washed with water, and solution decompression is concentrated into 400L, adds petroleum ether, is cooled to 15 DEG C, stirs 1-3h, filtering drying must be consolidated
Body LD-E.
Step (3)：The preparation of Lei Dipawei intermediate products 3-LD-F：
Synthesis flow：
Preparation process：LD-E is added into reaction kettle, tetrahydrofuran, is then heated to 32 DEG C by solution, is slowly added to contain
The tetrahydrofuran solution of potassium tert-butoxide so that 30 DEG C of internal temperature, reaction solution is stirred 28 minutes, then slow cooling to 20
DEG C, continue to stir 1h at 20 DEG C, filter, filter cake is washed with tetrahydrofuran, solid is obtained at 40 DEG C in vacuum drying 24h
To solid LD-F.
Step (4)：The preparation of Lei Dipawei intermediate products 4-LD-J：
(A1) prepared by LD-G
Synthesis flow：
Preparation process：LD-SM2,1-methyl-2-pyrrolidinone are added into reaction kettle, stirring adds bromine in batches to dissolving
Change reagent N-bromo-succinimide, then add catalyst benzoyl peroxide, controlling reaction temperature is at 60-70 DEG C, stirring
When reaction 7-9 is small, HPLC monitoring reactions are completed, and are cooled to 18-22 DEG C, are added water, be layered, lower floor's liquid, which adds methanol, to be had largely
Solid separates out, and white solid LD-G is dried to obtain in centrifugation；
(A2) prepared by LD-H
Synthesis flow：
Preparation process：LD-G and acetic acid are added in reaction kettle, are heated to 42 DEG C, and is stirred 30 minutes, dissolved clarification, is adjusted
Temperature of reaction kettle adds 20% sulfuric acid, is subsequently added into iodine, Potassiumiodate, 4h, HPLC are heated by reaction solution at 58 DEG C to after 25 DEG C
Monitoring reaction is completed, and reaction solution then is cooled to 22 DEG C, and 9% sodium sulfite solution is added in reaction mixture, is kept
Temperature continues to stir 1h, centrifugation, filter cake water wash is dry, obtains solid product LD-H at 25 DEG C；
(A3) prepared by LD-I
Synthesis flow：
Preparation process：Tetrahydrofuran, LD-H, N- fluorobenzenesulfonimide (NFSI) will be added in reaction kettle, stirring makes solid
Body dissolves, nitrogen displacement 3 times, under nitrogen protection, reaction solution is cooled to -70 DEG C, temperature is maintained at less than -65 DEG C dropwise addition fourths
The hexane solution (1.0M) of base lithium, drop finish, and (HPLC, which is monitored, to have reacted by -66 DEG C of internal temperature of control is following, and the reaction was continued 1.8h
Into), add methanol and reaction is quenched, after adjusting extremely -20 DEG C of temperature, HPLC is analysis shows that go out excessive N- oxo benzene carbimides
Completely consume, by temperature adjustment to 1 DEG C, add n-hexane, continue stirring 25 minutes, filtering, elutes filter cake with n-hexane, will filter
Liquid is concentrated in vacuo to 2.8 volumes below 28 DEG C, adds dichloromethane, is heated to reflux 50 minutes, mixture is concentrated into 4 bodies
Product, adds other methanol, and solution is again concentrated to 4 volumes, cools down, filtering, and with methanol elution twice, it is dry,
Obtain the product LD-I of solid.
(A4) preparation of grignard reagent
Synthesis flow：
Preparation process：Tetrahydrofuran is added into reaction kettle, magnesium chips, is heated to 50 DEG C, after temperature stabilization, addition contains THF
With the solution of isopropyl chloride, continue stirring to there is obvious heating；Continuing that the mixed liquor containing THF and isopropyl chloride is added dropwise, drop finishes, after
50 DEG C of stirring 3.5h of continuation of insurance temperature, the direct barrelling of the solution is in next step after cooling；
(A5) prepared by LD-J
Synthesis flow：
Preparation process：LD-I and tetrahydrofuran will be added in reaction kettle；Nitrogen displacement 3 times, under nitrogen protection, by solution
- 10 DEG C are cooled to, is slowly added to the THF solution of 2N isopropylmagnesium chlorides, gained reaction solution stirs 1.5h at -10 DEG C, until
The reaction was complete, and the chloro- N- methoxy N-methylacetamides of 2- are dissolved in methyl tertiary butyl ether(MTBE), then that 2- is chloro-
N- methoxy N-methylacetamide solution is slowly added in reaction kettle, and internal temperature is kept during dropwise addition, and at 5 DEG C, drop finishes, will
Internal temperature is adjusted to 1 DEG C, continues to stir 2h, after the completion of reaction, adds 1N hydrochloric acid, layering, and extracted with methyl tertiary butyl ether(MTBE)
Water layer, merges organic layer, is concentrated under reduced pressure into 10 volumes, and adjustment temperature stirs 2h to 22 DEG C, centrifuges, and use isopropanol
Filter cake is washed, it is dry, obtain the product LD-J of solid.
Step (5)：The preparation of Lei Dipawei intermediate products 5-LD-L：
(A1) prepared by LD-K
Synthesis flow：
Preparation process：By compound L D-J and compound L D-F, acetone is added in reaction kettle, is heated to 55 DEG C, and stir
Mix 2h to HPLC measure reactions to complete, be slowly added to water, and solution is kept for 30 minutes at 55 DEG C, be cooled to 20 DEG C, centrifuge,
And filter cake is washed with water, it is dry, obtain solid LD-K；
(A2) prepared by LD-L
Synthesis flow：
Preparation process：Compound L D-K, ammonium acetate, toluene and 2-methyl cellosolve are added into reaction kettle, by mixture
90 DEG C are heated to, and (HPLC monitorings) is completed in 90 DEG C of stirrings extremely reaction in 8 hours, solution is cooled to 55 DEG C, stirring to precipitation
Solid, adds normal heptane at 55 DEG C, then material is cooled to 21 DEG C in 3h, continues to stir 1h, filtering, and use normal heptane
Washing, is dried to obtain solid LD-L at 45 DEG C.
Step (6)：The preparation of bulk pharmaceutical chemicals Lei Dipawei-LD-Q：
(A1) prepared by LD-O
Synthesis flow：
Preparation process：Compound L D-M, double (pinacol) two boron, potassium propionate and tert-butyl diphenyl phosphine palladium bichloride are added
In reaction kettle, nitrogen displacement 3 times, adds isopropyl acetate, reaction mixture is heated to 75 DEG C, and stirs 3.5h, cools down
To after 25 DEG C, compound L D-L is added in reaction mixture, nitrogen displacement, the 1M potassium phosphate solutions of degassing are added into reactor
In, and reaction mixture is heated to 75 DEG C, continue to stir 1h, be subsequently cooled to 38 DEG C, add half Guangs of N- acetyl-L-
Propylhomoserin, continues to stir 1h, and reaction mixture is cooled to 20 DEG C, stops stirring, standing separation, separates water phase, and by N- second
Acyl-L-cysteine is added in organic layer, and reaction mixture is heated to 48 DEG C, mixture is stirred 2h at 48 DEG C, is cooled down
To 20 DEG C, and 5% sodium hydroxide solution is added, separate water phase, and organic layer is washed with 5% sodium chloride solution, depressurized
Concentration, adds isopropyl acetate, is heated to 50 DEG C afterwards, then adds the ethanol solution containing oxalic acid in mixture, and
When stirring 8 is small at 50 DEG C, filtering, and 45 DEG C of dryings under vacuo, obtain the LD-O of solid；
(A2) prepared by LD-P
Preparation process：Acetonitrile, LD-O are added into reaction kettle, 1.2N hydrochloric acid is added, by reaction mixture at 65 DEG C
The temperature of reaction mixture is adjusted to 45 DEG C by stirring 2h to completion (HPLC monitoring) is reacted, and is continued to stir 1h, is cooled to 20 DEG C,
Filtering, it is dry, obtain solid LD-P；
(A3) prepared by LD-Q
Preparation process：By 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate, I-hydroxybenzotriazole,
N- (methoxycarbonyl group)-Valine and n,N-Dimethylformamide are added in reaction kettle, and reaction mixture is stirred 1 at 23 DEG C
Hour, solution is then cooled to 1 DEG C, LD-P and N-methylmorpholine are added in reaction kettle, warms naturally to room temperature, and after
Continuous stirring 4h, adds ethyl acetate and water, layering, organic phase 5% sodium acid carbonate and water washing, then by organic layer distill to
2.5 volumes, are cooled to 23 DEG C, and acetone is added in reaction kettle, continue to stir 3h, centrifugation, filter cake is washed with acetone, dry, is obtained
To solid LD-Q.
Embodiment 3
A kind of preparation method of Lei Dipawei, includes the following steps：
Step (1)：The preparation of Lei Dipawei intermediate products 1-LD-B：
(A1) preparation of LD-A
Synthesis flow：
Preparation process：1% sodium hydrate aqueous solution, tetrahydrofuran and LD-SM1 are added into reaction kettle, stirs dissolved clarification, control
30 DEG C of system, the tetrahydrofuran solution of the acid anhydrides containing BOC is slowly dropped into reaction kettle, is dripped off and is controlled in insulation 30 DEG C of reactions 5h, HPLC
The reaction was complete, is layered organic phase saturated common salt water washing, is concentrated under reduced pressure, and obtains grease LD-A and throws in next step；
(A2) preparation of LD-B
Synthesis flow：
Preparation process：LD-A is added in reaction kettle, dichloromethane, is cooled to 2 DEG C, adds tetramethyl piperidine nitrogen oxides,
Then liquor natrii hypochloritis is slowly added into, while (HPLC monitorings) is completed in 5 DEG C of stirrings to reaction, then adds 12% sulfuric acid
Potassium solution, stirs 0.8h, layering, and organic phase is washed with 6% sodium thiosulfate solution and 18% salt, is concentrated under reduced pressure, and is remained
Thing adds petroleum ether, is maintained at 20 DEG C of stirring 3h, and filtration drying obtains solid LD-B.
Step (2)：The preparation of Lei Dipawei intermediate products 2-LD-E：
(A1) preparation of LD-C
Synthesis flow：
Preparation process：Diethylaminoethyl triphen phosphonium salt, 2- methyltetrahydrofurans, solid t-butyl alcohol are put into reaction kettle
Potassium, and 2 DEG C are maintained the temperature at, when 25 DEG C of stirrings 3 are small (holding suspension), 2 DEG C are cooled to, under conditions of 6 DEG C, is added
LD-B, when then reaction solution warms naturally to room temperature and small stirring 9, is cooled to 2 DEG C, adds 8% sodium bicarbonate solution stopped reaction,
Separate water layer, 6% sodium bicarbonate solution extraction of organic layer, the water layer of merging filters through diatomite, by water layer 10 DEG C with
6M hydrochloric acid is acidified, and is extracted 2 times with isopropyl acetate, is concentrated under reduced pressure into 400L, is added petroleum ether, when 30 DEG C of stirrings 2 are small, crossed and be filtered dry
It is dry to obtain solid LD-C；
(A2) prepared by LD-D
Synthesis flow：
Preparation process：By compound L D-C, benzyltrimethylammonium chloride, bromofom and dichloromethane are added in reaction kettle, are added
Enter 52% sodium hydroxide solution (control temperature is no more than 33 DEG C), when 32 DEG C of stirrings 3 are small, HPLC monitoring reactions are completed, cooling
To 22 DEG C, add water, stand 3h, branch vibration layer, and use 1M salt acid elution organic layers, organic layer is then washed with water, decompression
420L is concentrated into, petroleum ether is added and is cooled to 22 DEG C, stir 2h at 20 DEG C, filter, with petroleum ether filter cake, product is existed
It is dry at 42 DEG C, obtain the LD-D of solid；
(A3) prepared by LD-E
Synthesis flow：
Preparation process：A3. compound L D-D is added into reaction kettle, isopropanol, is then heated to 42 DEG C by reaction solution, will
Potassium hydroxide is added in solution, and is stirred until solid dissolves, and with nitrogen displacement 3 times, is then added 12% palladium carbon, is used hydrogen
Displacement 1 time, and 5 atmospheric pressure hydrogenations are kept at 42 DEG C, analyzed by HPLC and determine that reaction is completed, reaction is finished, and solution is cooled down
To 22 DEG C, and with nitrogen displacement 3 times, reacting liquid filtering is removed into solid, with water wash solid, solution is then concentrated into it
The half of initial volume, methylate tertbutyl ether and 4N hydrochloric acid extracting and demixings, water layer are extracted with methyl tertiary butyl ether(MTBE), are merged organic
Phase, is washed with water, and solution decompression is concentrated into 520L, adds petroleum ether, is cooled to 20 DEG C, stirs 3h, filtering drying obtains solid
LD-E。
Step (3)：The preparation of Lei Dipawei intermediate products 3-LD-F：
Synthesis flow：
Preparation process：LD-E is added into reaction kettle, tetrahydrofuran, is then heated to 35 DEG C by solution, is slowly added to contain
The tetrahydrofuran solution of potassium tert-butoxide so that internal temperature is no more than 40 DEG C, reaction solution is stirred 30 minutes, then slow cooling
To 22 DEG C, continue to stir 1.5h at 22 DEG C, filter, wash filter cake with tetrahydrofuran, solid is being dried in vacuo at 42 DEG C
26h, obtains solid LD-F.
Step (4)：The preparation of Lei Dipawei intermediate products 4-LD-J：
(A1) prepared by LD-G
Synthesis flow：
Preparation process：LD-SM2,1-methyl-2-pyrrolidinone are added into reaction kettle, stirring adds bromine in batches to dissolving
Change reagent N-bromo-succinimide, then add catalyst benzoyl peroxide, controlling reaction temperature is at 70 DEG C, stirring reaction
9 it is small when, HPLC monitoring reactions are completed, and are cooled to 22 DEG C, add water, and layering, lower floor's liquid, which adds methanol, has a large amount of solids to separate out,
White solid LD-G is dried to obtain in centrifugation；
(A2) prepared by LD-H
Synthesis flow：
Preparation process：LD-G and acetic acid are added in reaction kettle, are heated to 45 DEG C, and is stirred 35 minutes, dissolved clarification, is adjusted
Temperature of reaction kettle adds 22% sulfuric acid, is subsequently added into iodine to after 30 DEG C, and Potassiumiodate, 4.5h is heated by reaction solution at 60 DEG C,
HPLC monitoring reactions are completed, and reaction solution then is cooled to 25 DEG C, 10% sodium sulfite solution is added in reaction mixture,
30 DEG C are maintained the temperature at, continues to stir 1.5h, centrifugation, filter cake water wash is dry, obtains solid product LD-H；
(A3) prepared by LD-I
Synthesis flow：
Preparation process：Tetrahydrofuran, LD-H, N- fluorobenzenesulfonimide (NFSI) will be added in reaction kettle, stirring makes solid
Body dissolves, nitrogen displacement 3 times, under nitrogen protection, reaction solution is cooled to -65 DEG C, temperature is maintained at -58 DEG C of dropwise addition butyl lithiums
Hexane solution (1.0M), drop finishes, and controls -66 DEG C of internal temperature, the reaction was continued 2h (HPLC monitoring reactions are completed), adds first
Reaction is quenched in alcohol, and after adjusting extremely -18 DEG C of temperature, HPLC is completely consumed analysis shows that going out excessive N- oxo benzene carbimides, will
Temperature adjustment adds n-hexane to 2 DEG C, continues stirring 30 minutes, and filtering, filter cake is eluted with n-hexane, and filtrate is true at 23 DEG C
Sky is concentrated into 3.0 volumes, adds dichloromethane, is heated to reflux 60 minutes, mixture is concentrated into 4.5 volumes, is added other
Methanol, and solution is again concentrated to 4.5 volumes, cools down, filtering, and with methanol elution twice, it is dry, obtain the production of solid
Thing LD-I.
(A4) preparation of grignard reagent
Synthesis flow：
Preparation process：Tetrahydrofuran is added into reaction kettle, magnesium chips, is heated to 55 DEG C, after temperature stabilization, addition contains THF
With the solution of isopropyl chloride, continue stirring to there is obvious heating；Continuing that the mixed liquor containing THF and isopropyl chloride is added dropwise, drop finishes, after
55 DEG C of stirring 4h of continuation of insurance temperature, the direct barrelling of the solution is in next step after cooling；
(A5) prepared by LD-J
Synthesis flow：
Preparation process：LD-I and tetrahydrofuran will be added in reaction kettle；Nitrogen displacement 3 times, under nitrogen protection, by solution
- 8 DEG C are cooled to, is slowly added to the THF solution of 2N isopropylmagnesium chlorides, gained reaction solution stirs 2h at -8 DEG C, until reaction
Completely, the chloro- N- methoxy N-methylacetamides of 2- are dissolved in methyl tertiary butyl ether(MTBE), then by the chloro- N- first of 2-
Epoxide-N- methyl vinyl amine aqueous solutions are slowly added in reaction kettle, and internal temperature is kept during dropwise addition, and at 0 DEG C, drop finishes, will internal temperature
Degree be adjusted to 2 DEG C, continue stir 2h, after the completion of reaction, add 1N hydrochloric acid, layering, and use methyl tertiary butyl ether(MTBE) aqueous layer extracted, conjunction
And organic layer, 10 volumes are concentrated under reduced pressure into, adjustment temperature stirs 2.5h to 25 DEG C, centrifuges, and wash filter with isopropanol
Cake, it is dry, obtain the product LD-J of solid.
Step (5)：The preparation of Lei Dipawei intermediate products 5-LD-L：
(A1) prepared by LD-K
Synthesis flow：
Preparation process：By compound L D-J and compound L D-F, acetone is added in reaction kettle, is heated to 60 DEG C, and stir
Mix 2.5h to HPLC measure reactions to complete, be slowly added to water, and solution is kept for 35 minutes at 60 DEG C, be cooled to 25 DEG C, from
The heart, and filter cake is washed with water, it is dry, obtain solid LD-K；
(A2) prepared by LD-L
Synthesis flow：
Preparation process：Compound L D-K, ammonium acetate, toluene and 2-methyl cellosolve are added into reaction kettle, by mixture
95 DEG C are heated to, and (HPLC monitorings) is completed in 95 DEG C of stirrings extremely reaction in 9 hours, solution is cooled to 60 DEG C, stirring to precipitation
Solid, adds normal heptane at 60 DEG C, then material is cooled to 22 DEG C in 3.5h, continues to stir 1.5h, filters, and with just
Heptane wash, is dried to obtain solid LD-L at 50 DEG C.
Step (6)：The preparation of bulk pharmaceutical chemicals Lei Dipawei-LD-Q：
(A1) prepared by LD-O
Synthesis flow：
Preparation process：Compound L D-M, double (pinacol) two boron, potassium propionate and tert-butyl diphenyl phosphine palladium bichloride are added
In reaction kettle, nitrogen displacement 3 times, adds isopropyl acetate, reaction mixture is heated to 80 DEG C, and stirs 4h, is cooled to
After 30 DEG C, compound L D-L is added in reaction mixture, nitrogen displacement, the 1M potassium phosphate solutions of degassing are added into reactor
In, and reaction mixture is heated to 80 DEG C, continue to stir 1.5h, be subsequently cooled to 40 DEG C, add N- acetyl-L- half
Cystine, continues to stir 1.5h, and reaction mixture is cooled to 22 DEG C, stops stirring, standing separation, separates water phase, and will
N-acetyl-L-cysteine is added in organic layer, and reaction mixture is heated to 50 DEG C, mixture is stirred at 50 DEG C
2.5h, is cooled to 22 DEG C, and adds 6% sodium hydroxide solution, separates water phase, and washed with 6% sodium chloride solution
Machine layer, is concentrated under reduced pressure, and adds isopropyl acetate afterwards, is heated to 55 DEG C, and the ethanol solution containing oxalic acid then is added mixture
In, and when stirring 9 is small at 55 DEG C, filtering, and 50 DEG C of dryings under vacuo obtain the LD-O of solid；
(A2) prepared by LD-P
Preparation process：Acetonitrile, LD-O are added into reaction kettle, 1.2N hydrochloric acid is added, by reaction mixture at 70 DEG C
The temperature of reaction mixture is adjusted to 50 DEG C by stirring 2.5h to completion (HPLC monitoring) is reacted, and is continued to stir 1.5h, is cooled to 22
DEG C, filter, it is dry, obtain solid LD-P；
(A3) prepared by LD-Q
Preparation process：By 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate, I-hydroxybenzotriazole,
N- (methoxycarbonyl group)-Valine and n,N-Dimethylformamide are added in reaction kettle, and reaction mixture is stirred at 26 DEG C
1.5 it is small when, solution is then cooled to 2 DEG C, LD-P and N-methylmorpholine are added in reaction kettle, warm naturally to room temperature, and
And continue to stir 4.5h, add ethyl acetate and water, layering, organic phase 6% sodium acid carbonate and water washing, then by organic layer
Distillation is cooled to 26 DEG C, acetone is added in reaction kettle, continue to stir 3.5h, centrifugation, filter cake is washed with acetone, is done to 3 volumes
It is dry, obtain solid LD-Q.
The better embodiment of the present invention is explained in detail above, but the present invention is not limited to above-mentioned embodiment party
Formula, can also be on the premise of present inventive concept not be departed from the knowledge that one skilled in the relevant art possesses
Various changes can be made.
Claims (7)
1. a kind of preparation method of Lei Dipawei, it is characterised in that include the following steps：Step (1)：Lei Dipawei intermediates produce
The preparation of product 1-LD-B：
(A1) preparation of LD-A
(A2) preparation of LD-B
Step (2)：The preparation of Lei Dipawei intermediate products 2-LD-E：
(A1) preparation of LD-C
(A2) prepared by LD-D
(A3) prepared by LD-E
Step (3)：The preparation of Lei Dipawei intermediate products 3-LD-F：
Step (4)：The preparation of Lei Dipawei intermediate products 4-LD-J：(A1) prepared by LD-G
(A2) prepared by LD-H
(A3) prepared by LD-I
(A4) preparation of grignard reagent
(A5) prepared by LD-J
Step (5)：The preparation of Lei Dipawei intermediate products 5-LD-L：(A1) prepared by LD-K
(A2) prepared by LD-L
Step (6)：The preparation of bulk pharmaceutical chemicals Lei Dipawei-LD-Q：
(A1) prepared by LD-O
(A2) prepared by LD-P
(A3) prepared by LD-Q
A kind of 2. preparation method of Lei Dipawei according to claim 1, it is characterised in that the specific steps of step (1)
For：
A1. 19-21% sodium hydrate aqueous solutions, tetrahydrofuran and LD-SM1 are added into reaction kettle, stirs dissolved clarification, controls 20-
30 DEG C, the tetrahydrofuran solution of the acid anhydrides containing BOC is slowly dropped into reaction kettle, dripped off in insulation 20-30 DEG C of reaction 4-5h, HPLC
The reaction was complete for control, is layered organic phase saturated common salt water washing, is concentrated under reduced pressure, and obtains grease LD-A and throws in next step；
A2. LD-A is added in reaction kettle, dichloromethane, is cooled to 0-2 DEG C, adds tetramethyl piperidine nitrogen oxides, then slowly
Liquor natrii hypochloritis is added, while (HPLC monitorings) is completed in 0-5 DEG C of stirring to reaction, the potassium sulfate for then adding 8-12% is molten
Liquid, stirs 0.3-0.8h, layering, and organic phase is washed with the salt of 4-6% sodium thiosulfate solutions and 12-18%, is concentrated under reduced pressure,
Residue adds petroleum ether, is maintained at 10-20 DEG C of stirring 1-3h, and filtration drying obtains solid LD-B.
A kind of 3. preparation method of Lei Dipawei according to claim 1, it is characterised in that the specific steps of step (2)
For：
A1. Diethylaminoethyl triphen phosphonium salt, 2- methyltetrahydrofurans, solid potassium tert-butoxide are put into reaction kettle, and keeps temperature
Degree when 15-25 DEG C of stirring 1-3 is small (holding suspension), is cooled to 0-2 DEG C, under conditions of less than 6 DEG C, adds at 0-2 DEG C
LD-B, then reaction solution warm naturally to room temperature and stir 7-9 it is small when, be cooled to 0-2 DEG C, add in 6-8% sodium bicarbonate solutions
Only react, separate water layer, organic layer is extracted with 7% sodium bicarbonate solution, and the water layer of merging filters through diatomite, water layer is existed
Less than 10 DEG C are acidified with 6M hydrochloric acid, are extracted 2 times with isopropyl acetate, are concentrated under reduced pressure into 400L, add petroleum ether, 20-30 DEG C is stirred
Mix 1-2 it is small when, filtration drying obtains solid LD-C；
A2. compound L D-C, benzyltrimethylammonium chloride, bromofom and dichloromethane are added in reaction kettle, adds 48-52% hydrogen
Sodium hydroxide solution (control temperature is no more than 38 DEG C), when 28-32 DEG C of stirring 1-3 is small, HPLC monitoring reactions are completed, and are cooled to
18-22 DEG C, water is added, stands 1-3h, branch vibration layer, and with 1M salt acid elution organic layers, organic layer is then washed with water, subtracts
Pressure is concentrated into 380-420L, adds petroleum ether and is cooled to 18-22 DEG C, stirs 2h at 18-20 DEG C, filter, use petroleum ether
Filter cake, by product, the drying at 38-42 DEG C, obtains the LD-D of solid；
A3. compound L D-D is added into reaction kettle, isopropanol, is then heated to 38-42 DEG C by reaction solution, by potassium hydroxide plus
Enter in solution, and stir until solid dissolves, with nitrogen displacement 3 times, then add 8-12% palladium carbons, replaced 1 time with hydrogen,
And 2-5 atmospheric pressure hydrogenation is kept at 38-42 DEG C, analyzed by HPLC and determine that reaction is completed, reaction is finished, and solution is cooled to
20-22 DEG C, and with nitrogen displacement 3 times, reacting liquid filtering is removed into solid, with water wash solid, is then concentrated into solution
The half of its initial volume, methylate tertbutyl ether and 4N hydrochloric acid extracting and demixings, water layer are extracted with methyl tertiary butyl ether(MTBE), are associated with
Machine phase, is washed with water, and solution decompression is concentrated into 480-520L, adds petroleum ether, is cooled to 10-20 DEG C, stirs 1-3h, filtering
Dry to obtain solid LD-E.
A kind of 4. preparation method of Lei Dipawei according to claim 1, it is characterised in that the specific steps of step (3)
For：
LD-E is added into reaction kettle, tetrahydrofuran, is then heated to 30-35 DEG C by solution, is slowly added to containing potassium tert-butoxide
Tetrahydrofuran solution so that internal temperature is no more than 40 DEG C, reaction solution is stirred 25-30 minutes, then slow cooling to 18-22
DEG C, continue to stir 0.5-1.5h at 18-22 DEG C, filter, filter cake is washed with tetrahydrofuran, by solid true at 38-42 DEG C
The dry 22-26h of sky, obtains solid LD-F.
A kind of 5. preparation method of Lei Dipawei according to claim 1, it is characterised in that the specific steps of step (4)
For：
A1. LD-SM2,1-methyl-2-pyrrolidinone are added into reaction kettle, stirring adds bromide reagent N- bromines in batches to dissolving
For succimide, catalyst benzoyl peroxide is then added, for controlling reaction temperature at 60-70 DEG C, stirring reaction 7-9 is small
When, HPLC monitoring reactions are completed, and are cooled to 18-22 DEG C, add water, and layering, lower floor's liquid, which adds methanol, has a large amount of solids to separate out,
White solid LD-G is dried to obtain in centrifugation；
A2. LD-G and acetic acid are added in reaction kettle, is heated to 40-45 DEG C, and stirred 25-35 minutes, dissolved clarification, adjust reaction
Kettle temperature degree adds 18-22% sulfuric acid, is subsequently added into iodine, Potassiumiodate, reaction solution is heated at 56-60 DEG C to after 20-30 DEG C
3.5-4.5h, HPLC monitoring reaction are completed, and reaction solution then is cooled to 20-25 DEG C, the sodium sulfite solution of 8-10% is added
Enter in reaction mixture, maintain the temperature at 20-30 DEG C, continue to stir 0.5-1.5h, centrifugation, filter cake water wash is dry, obtains
Solid product LD-H；
A3. tetrahydrofuran, LD-H, N- fluorobenzenesulfonimide (NFSI) will be added in reaction kettle, stirring dissolves solid, nitrogen
Gas is replaced 3 times, under nitrogen protection, reaction solution is cooled to -75- (- 65) DEG C, temperature is maintained at less than less than -55 DEG C dropwise additions
The hexane solution (1.0M) of butyl lithium, drop finish, and (HPLC monitoring is instead by -60 DEG C of internal temperature of control is following, and the reaction was continued 1.5-2h
Should complete), add methanol and reaction is quenched, after adjusting extremely -22- (- 18) DEG C of temperature, HPLC is analysis shows that go out excessive N- oxos
Benzene carbimide completely consumes, by temperature adjustment to 0-2 DEG C, add n-hexane, continue stirring 20-30 minute, filter, use just oneself
Alkane elutes filter cake, and filtrate is concentrated in vacuo to 2.5-3.0 volumes below 28 DEG C, adds dichloromethane, is heated to reflux 40-60 points
Clock, 3.5-4.5 volumes are concentrated into by mixture, add other methanol, and solution is again concentrated to 3.5-4.5 volumes, drop
Temperature, filtering, and with methanol elution twice, it is dry, obtain the product LD-I of solid.
A4. tetrahydrofuran is added into reaction kettle, magnesium chips is heated to 45-55 DEG C, and after temperature stabilization, addition contains THF and isopropyl
The solution of chlorine, continues stirring to there is obvious heating；Continue that the mixed liquor containing THF and isopropyl chloride is added dropwise, drop finishes, continues to keep the temperature
45-55 DEG C of stirring 3-4h, the direct barrelling of the solution is in next step after cooling；
A5. LD-I and tetrahydrofuran will be added in reaction kettle；Nitrogen displacement 3 times, under nitrogen protection, -12- is cooled to by solution
(- 8) DEG C, are slowly added to the THF solution of 2N isopropylmagnesium chlorides, and gained reaction solution stirs 1-2h at -12- (- 8) DEG C, until
The reaction was complete, and the chloro- N- methoxy N-methylacetamides of 2- are dissolved in methyl tertiary butyl ether(MTBE), then that 2- is chloro-
N- methoxy N-methylacetamide solution is slowly added in reaction kettle, and internal temperature is kept during dropwise addition at -10 DEG C to 0 DEG C,
Drop finishes, and internal temperature is adjusted to 0-2 DEG C, continues to stir 2h, after the completion of reaction, adds 1N hydrochloric acid, layering, and with methyl- tert fourth
Base ether aqueous layer extracted, merges organic layer, is concentrated under reduced pressure into 10 volumes, and adjustment temperature stirs 1.5-2.5h to 20-25 DEG C,
Centrifugation, and filter cake is washed with isopropanol, it is dry, obtain the product LD-J of solid.
A kind of 6. preparation method of Lei Dipawei according to claim 1, it is characterised in that the specific steps of step (5)
For：
A1. compound L D-J and compound L D-F, acetone are added in reaction kettle, is heated to 50-60 DEG C, and stir 1.5-
2.5h to HPLC measure reactions are completed, and are slowly added to water, and solution is kept for 25-35 minutes at 50-60 DEG C, are cooled to 15-
25 DEG C, centrifugation, and filter cake is washed with water, and it is dry, obtain solid LD-K；
A2. compound L D-K, ammonium acetate, toluene and 2-methyl cellosolve are added into reaction kettle, heats the mixture to 85-
95 DEG C, and (HPLC monitorings) is completed in 85-95 DEG C of stirring extremely reaction in 7-9 hours, solution is cooled to 50-60 DEG C, stirring to analysis
Go out solid, normal heptane is added at 50-60 DEG C, material is then cooled to 20-22 DEG C in 2.5-3.5h, continue to stir 0.5-
1.5h, filtering, and washed with normal heptane, solid LD-L is dried to obtain at 40-50 DEG C.
A kind of 7. preparation method of Lei Dipawei according to claim 1, it is characterised in that the specific steps of step (6)
For：
A1. compound L D-M, double (pinacol) two boron, potassium propionate and tert-butyl diphenyl phosphine palladium bichloride are added in reaction kettle,
Nitrogen displacement 3 times, adds isopropyl acetate, reaction mixture is heated to 70-80 DEG C, and stirs 3-4h, is cooled to 20-30
After DEG C, compound L D-L is added in reaction mixture, nitrogen displacement, the 1M potassium phosphate solutions of degassing is added in reactor,
And reaction mixture is heated to 70-80 DEG C, continues to stir 0.5-1.5h, is subsequently cooled to 35-40 DEG C, add N- second
Acyl-L-cysteine, continues to stir 0.5-1.5h, and reaction mixture is cooled to 18-22 DEG C, stops stirring, standing separation,
Water phase is separated, and N-acetyl-L-cysteine is added in organic layer, reaction mixture is heated to 45-50 DEG C, will be mixed
Compound stirs 1.5-2.5h at 45-50 DEG C, is cooled to 18-22 DEG C, and adds the sodium hydroxide solution of 4-6%, separates water
Phase, and organic layer is washed with 4-6% sodium chloride solutions, it is concentrated under reduced pressure, adds isopropyl acetate afterwards, is heated to 45-55 DEG C,
Then the ethanol solution containing oxalic acid is added in mixture, and stir at 45-55 DEG C 7-9 it is small when, filtering, and in vacuum
Lower 40-50 DEG C of drying, obtains the LD-O of solid；
A2. acetonitrile, LD-O are added into reaction kettle, 1.2N hydrochloric acid is added, reaction mixture is stirred into 1.5- at 60-70 DEG C
The temperature of reaction mixture is adjusted to 40-50 DEG C by 2.5h to completion (HPLC monitoring) is reacted, and continues to stir 0.5-1.5h, cooling
To 18-22 DEG C, filter, it is dry, obtain solid LD-P；
A3. by 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate, I-hydroxybenzotriazole, N- (methoxy carbonyls
Base)-Valine and n,N-Dimethylformamide added in reaction kettle, reaction mixture is stirred into 0.5-1.5 at 20-26 DEG C
Hour, solution is then cooled to 0-2 DEG C, LD-P and N-methylmorpholine are added in reaction kettle, warm naturally to room temperature, and
Continue to stir 3.5-4.5h, add ethyl acetate and water, layering, organic phase 4-6% sodium acid carbonates and water washing, then will have
Machine layer is distilled to 2-3 volumes, is cooled to 20-26 DEG C, and acetone is added in reaction kettle, continues to stir 2.5-3.5h, centrifugation, filter cake
Washed with acetone, it is dry, obtain solid LD-Q.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108530262A (en) * | 2018-06-15 | 2018-09-14 | 贾红琴 | A kind of synthetic method of 2- bromines fluorenes |
| CN115515936A (en) * | 2020-03-27 | 2022-12-23 | 罗达制药生物技术有限责任公司 | Process for the preparation of (R) -4- (1- (6- (4- (trifluoromethyl) benzyl) -6-azaspiro [2.5] octane-5-carboxamido) -cyclopropyl) benzoic acid or a salt thereof |
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| CN101316852A (en) * | 2005-08-26 | 2008-12-03 | 弗特克斯药品有限公司 | Inhibitors of serine proteases |
| CN104520293A (en) * | 2012-06-05 | 2015-04-15 | 吉利德法莫赛特有限责任公司 | Synthesis of antiviral compound |
| CN105801462A (en) * | 2014-12-29 | 2016-07-27 | 重庆博腾制药科技股份有限公司 | (4S)-N-Boc-4-methoxymethyl-L-proline synthesis method |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101316852A (en) * | 2005-08-26 | 2008-12-03 | 弗特克斯药品有限公司 | Inhibitors of serine proteases |
| CN104520293A (en) * | 2012-06-05 | 2015-04-15 | 吉利德法莫赛特有限责任公司 | Synthesis of antiviral compound |
| CN105801462A (en) * | 2014-12-29 | 2016-07-27 | 重庆博腾制药科技股份有限公司 | (4S)-N-Boc-4-methoxymethyl-L-proline synthesis method |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108530262A (en) * | 2018-06-15 | 2018-09-14 | 贾红琴 | A kind of synthetic method of 2- bromines fluorenes |
| CN115515936A (en) * | 2020-03-27 | 2022-12-23 | 罗达制药生物技术有限责任公司 | Process for the preparation of (R) -4- (1- (6- (4- (trifluoromethyl) benzyl) -6-azaspiro [2.5] octane-5-carboxamido) -cyclopropyl) benzoic acid or a salt thereof |
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Application publication date: 20180424 |