A kind of be atp competitiveness small molecule akt inhibitor a443654 synthetic method
Technical field:
The present invention relates to a kind of preparation method of compound, particularly a kind of atp competitiveness small molecule akt inhibitor
The synthetic method of a443654.
Background technology:
Pi3k/akt/mtor signal path is intracellular important signal transduction pathway, the impact metabolism of cell, increment,
Transcription, survival and the aspect such as Angiogenesiss, have close relationship with the occurrence and development of various tumours, and also with glycosuria
Disease, disease of cardiovascular system are relevant.Akt is also called protein kinase b (protein kinase b, pkb), be a kind of serine/
Serineprotein kinase.Pi3k/akt signal transduction is in the state of activation in the normal tissue, and when this path excessive activation,
P-akt over-expresses, then may be by lowering the modes such as tumor suppressor protein p53, stimulating protein synthesis, inhibited apoptosis
Lead to the unlimited increment of tumour cell.Therefore suppress the activation of this path, the programmed cell death of cancer cell can be promoted, be conducive to tumour
Treatment.Various small molecule akt inhibitor are reported the clinical research entering oncotherapy, such as breast cancer, prostatitis successively at present
Gland cancer, myelogenous leukemia, lymphocytic leukemia, myeloma etc..
A443654 is the representative of atp competitiveness small molecule akt inhibitor, will be used for the treatment of multiple solid tumors.Its chemistry
Entitled (s) -1- (1h- indol-3-yl) -3- (5- (3- methyl isophthalic acid h- indazole -5- base) pyridin-3-yl epoxide) propyl- 2- amine, English
Entitled (s) -1- (1h-indol-3-yl) -3- [5- (3-methyl-1h-indazol-5-yl) pyridin-3-yloxy]
Propan-2-amine, its structural formula is as shown in Equation 6:
According to patent us20030199511 and document bioorganic&medicinal chemistry 2006,14,
6832 6846 reports, disclose a kind of preparation method of a-443654, flow chart as shown in Figure 1.
The method, with compound 4 as initiation material, obtains compound 6 through 3 step reactions, total recovery is 13%.This synthesizes road
The shortcoming of line is to have used highly toxic hexa methyl ditin reagent, and the preparation reaction time length of tin reagent intermediate 5a, receipts
Rate is low.Whole piece route economy is low, total recovery is low, process costs are high, environment is unfriendly, be unfavorable for that industrialization is amplified.
In view of there is reactions steps complexity, technology high cost, overall yield in the synthetic method having prepared this compound 6
Low shortcoming it is therefore desirable to develop a kind of more economical, efficiently, environmental protection, easy variation route, be beneficial to industrialized production.
Content of the invention
The invention discloses a kind of synthetic method of atp competitiveness small molecule akt inhibitor a443654, the method is to change
Compound 1 is initiation material, obtains compound 6 (a-443654) and (sees below through amido protecting, suzuki reaction, protection group removing
Figure).This method avoid the use of poisonous reagent hexa methyl ditin, security is good, environmentally friendly, and when shortening reaction
Between, reaction yield is high, reduce process costs, be suitable for industrialization large-scale production.
With reference to specific embodiment, the present invention is expanded on further.It should be understood that these embodiments are merely to illustrate the present invention
Rather than restriction the scope of the present invention.The experimental technique of unreceipted actual conditions in the following example, generally according to conventional strip
Part is carried out.
In embodiment, raw material used or reagent are in addition to special instruction, all commercially available.
Room temperature described in embodiment refers both to 20~35 DEG C.Unless otherwise indicated, described reagent is not purified directly makes
With.All solvents are purchased from commercialization supplier, such as aldrich (aldrich), and not treated can use.Reaction
Analyzed by tlc and/or analyzed by lc-ms, judge the termination reacted by the consumption of parent material.The thin layer of analysis
Chromatography (tlc) is the glass plate (emd chemical company (emd chemicals)) in pre-coated silica gel 60f2540.25 millimeter plate
On carry out, with the iodine developing on uv light (254nm) and/or silica gel, and/or with tlc product dyed thereby such as alcohol phosphomolybdic acid, hydration indenes
Triketone solution, liquor potassic permanganate or ceric sulfate solution heat together.
1h-nmr spectrum is on ten thousand Ruian-Mo Qiuli-vx400 (varian mercury-vx400) instrument, in 400mhz behaviour
Make lower record.
Used in the present invention, abbreviation has this area conventional sense, such as: dcm represents dichloromethane, and dmso represents diformazan
Base sulfoxide.
The preparation method of the present invention can be represented with the flow process shown in accompanying drawing 2.
More specifically, the preparation method of the present invention comprises following process:
1) compound 1 in the basic conditions, is reacted with conventional amido protecting agent, prepared compound 2.
Wherein r defines with accompanying drawing 2.
Described alkali can be sodium carbonate, potassium carbonate, cesium carbonate, sodium acid carbonate, saleratus, NaOH, potassium hydroxide,
Lithium hydroxide, the inorganic base such as barium hydroxide, or the organic base such as pyridine, triethylamine, diisopropyl ethyl amine, or p-methyl benzenesulfonic acid pyrrole
Pyridine, wherein it is preferred that triethylamine.The molar feed ratio of described alkali and compound 1 is 0.05~15:1, preferably 0.05~
5:1.
Amido protecting agent can be di-tert-butyl dicarbonate (boc2O), benzyl chloroformate (cbzcl), chloro-carbonic acid -9- fluorenes
Base methyl esters (fmoc-cl), allyl chlorocarbonate (alloc-cl), dihydro pyranyl (dhp), n- [2- (trimethyl silicon substrate) ethoxy
Carbonyloxy group] succinimide (teoc succinimide) etc., wherein it is preferred that di-tert-butyl dicarbonate or benzyl chloroformate or
Dihydro pyranyl (dhp).The molar feed ratio of described amido protecting agent and compound 1 is 1~10:1, preferably 1~3:1.
Reaction temperature is room temperature to solvent reflux temperature, preferably reflux temperature.
The solvent being suitable for above-mentioned reaction is acetonitrile, dichloromethane, ethanol, methyl alcohol, oxolane, dmf, dioxane, second
Acetoacetic ester, toluene, any combination of chloroform etc. or above-mentioned solvent.A kind of preferred solvent is chloroform.
2) in the basic conditions, palladium reagent catalysis is lower and connection boric acid pinacol ester occurs suzuki coupling reaction for compound 2,
Prepared compound 3.
Wherein r defines with accompanying drawing 2.
Described alkali can be sodium carbonate, potassium carbonate, cesium carbonate, sodium acid carbonate, saleratus, NaOH, potassium hydroxide,
Lithium hydroxide, potassium tert-butoxide, sodium tert-butoxide, the inorganic base such as potassium acetate, or pyridine, triethylamine, diisopropyl ethyl amine etc. are organic
Alkali, wherein it is preferred that potassium acetate, and described alkali is 1~10:1, preferably 1~3:1 with the molar feed ratio of compound 2.
Described palladium reagent can be pd (dppf) cl2, pd2(dba)3, pd (pph3)4, pd (oh)2, pd (oac)2, wherein excellent
Choosing is pd (dppf) cl2.Described palladium reagent is 0.01~0.5:1 with the molar feed ratio of compound 2, preferably 0.05~
0.3:1.
Reaction temperature is room temperature to solvent reflux temperature, preferably reflux temperature.
The solvent being suitable for above-mentioned reaction is dmso, acetonitrile, dichloromethane, ethanol, methyl alcohol, oxolane, dmf, dioxy six
Ring, ethyl acetate, any combination of toluene etc. or above-mentioned solvent.A kind of preferred solvent is dmso.
The molar feed ratio of connection boric acid pinacol ester and compound 2 is 1~10:1, excellent for electing 1~1.5:1 as.
Reaction time detecting that reaction completes, usually 1~48 hour, preferably 12~16 hours.
3) compound 4 and compound 3, under conditions of alkali, carries out suzuki coupling reaction, preparedization under palladium reagent catalysis
Compound 5.
Wherein r defines with accompanying drawing 2.
Described alkali can be sodium carbonate, potassium carbonate, cesium carbonate, sodium acid carbonate, saleratus, NaOH, potassium hydroxide,
Lithium hydroxide, potassium tert-butoxide, sodium tert-butoxide, the inorganic base such as potassium acetate, or pyridine, triethylamine, diisopropyl ethyl amine etc. are organic
Alkali, wherein it is preferred that sodium carbonate, and described alkali is 1~10:1, preferably 1~4:1 with the molar feed ratio of compound 4.
Described palladium reagent can be pd (dppf) cl2, pd2(dba)3, pd (pph3)4, pd (oh)2, pd (oac)2, wherein excellent
Choosing is pd (dppf) cl2.Described palladium reagent is 0.01~0.5:1 with the molar feed ratio of compound 2, preferably 0.03~
0.3:1.
Reaction temperature is room temperature to solvent reflux temperature, preferably reflux temperature.
The solvent being suitable for above-mentioned reaction is dmso, acetonitrile, dichloromethane, ethanol, methyl alcohol, oxolane, dmf, dioxy six
Ring, ethyl acetate, toluene, any combination of water etc. or above-mentioned solvent.A kind of preferred solvent is the mixing of dioxane and water
Thing.
The volume ratio of dioxane and water is 10~1:1, excellent for electing 3~1:1 as.
Compound 3 is 1~10:1 with the molar feed ratio of compound 4, excellent for electing 1~1.2:1 as.
Reaction time detecting that reaction completes, usually 1~48 hour, preferably 12~16 hours.
4) compound 5 sloughs amino protecting group, prepared compound 6, and the described method of Deprotection and condition can be this
The conventional method of the such reaction in field and condition.
The advantage of the inventive method essentially consists in:
1) avoid the use of high toxicity hexa methyl ditin reagent, and use eco-friendly borane reagent instead.
2) preparation of contrast existing report method key tin reagent intermediate, the preparation of borane reagent intermediate in the method
Reaction time greatly shortens, and yield increases substantially.
3) committed step suzuki coupling reaction, easy and simple to handle, yield is up to 73%, and whole piece synthetic route gross production rate is
63%.
This method is a brand-new synthetic route capable of being industrialized.Meanwhile, this route has to developing new inhibitor
Methodology meaning well.
Brief description
Fig. 1 is the flow chart of a-443654 synthetic method disclosed in patent us20030199511;
Fig. 2 is the flow chart of akt inhibitor a443654 synthetic method of the present invention, wherein: r be THP trtrahydropyranyl (thp) or
Person's tertbutyloxycarbonyl (boc) or benzyloxycarbonyl group (cbz), fluorenylmethyloxycarbonyl (fmoc) or allyloxycarbonyl (alloc) or
Trimethylsilyl ethoxycarbonyl (teoc).
Specific embodiments
With reference to specific embodiment, the present invention is expanded on further.It should be understood that these embodiments are merely to illustrate the present invention
Rather than restriction the scope of the present invention.The experimental technique of unreceipted actual conditions in the following example, generally according to conventional strip
Part is carried out.
Embodiment 1: the preparation of compound 2
Addition compound 1 (50g, 237mmol, 1eq) in 500ml there-necked flask, 3,4- dihydropyran (60g, 713mmol,
3eq), p-methyl benzenesulfonic acid pyridine (3g, 11.8mmol, 0.05eq), chloroform (250ml, 5v), it is heated to back flow reaction 3 hours,
Tlc detection raw material reaction is complete.Reaction system is down to room temperature, adds saturated sodium bicarbonate aqueous solution (500ml), stirs 5 minutes,
Standing, separates organic phase, aqueous phase chloroform (200ml) extracts 1 time again, merges organic phase, with saturated aqueous common salt (500ml) and water
(500ml) respectively wash once, anhydrous sodium sulfate drying, be concentrated to give black liquor (70g, y=100%).
1h nmr(cdcl3,500mhz):δppm 7.72(s,1h),7.53(s,1h),7.29(s,1h),5.62(m,
1h),4.10(m,1h),3.73(m,1h),2.63(s,3h),2.19(m,1h),2.09(m,1h),1.65(m,4h);esi/ms:
M/z=295 (m+h)+.
Embodiment 2: the preparation of compound 3
In the there-necked flask of 1l, addition compound 2 (50g, 168.8mmol, 1eq), connection boric acid pinacol ester (45g,
177.3mmol, 1.05eq), potassium acetate (50g, 506.5mmol, 3eq) and dmso (500ml), stir under nitrogen protection
15min, adds pd (dppf) cl2(6.9g, 8.44mmol, 0.05eq), nitrogen displacement, it is heated to 70 DEG C, reaction overnight.lcms
Monitoring raw material reaction is complete, is down to room temperature, adds water (500ml), ethyl acetate (500ml), silica gel (50g), mistake after stirring 5 minutes
Filter.Separate organic phase, aqueous phase ethyl acetate (500ml) extracts 1 time again.Merge organic phase, washed once with saturated common salt, no
Aqueous sodium persulfate is dried, and is concentrated to give black liquor 57.1g, y=100%).Without purifying, it is directly used in the next step.
1h nmr(cdcl3,500mhz):δppm 8.32(s,1h),8.13(s,1h),7.62(s,1h),5.80(m,
1h),4.13(m,1h),3.83(m,1h),2.65(s,3h),2.23(m,1h),2.12(m,1h),1.75(m,4h),1.25(s,
12h);Esi/ms:m/z=343 (m+h)+.
Embodiment 3: the preparation of compound 5
In 3l there-necked flask, add compound 4 (150g, 336mmol, 1eq), compound 3 (138g, 403.3mmol,
1.2eq), sodium carbonate (142.5g, 1344.3mmol, 4eq), dioxane (900ml, 6v), water (600ml, 4v), nitrogen is protected
Lower addition pd (dppf) cl2(8.2g, 10.1mmol, 0.03eq), nitrogen displacement, then heat to 75 degree of reaction overnight.lcms
Monitoring raw material reaction is complete.Add water (1.5l), ethyl acetate (1.5l), silica gel (150g), stir 10min, filter, filtrate is divided
Go out organic layer, aqueous phase is extracted 1 time with ethyl acetate (1.5l), merge organic phase, organic phase saturated aqueous common salt (1.5l) washes 1
Secondary, anhydrous sodium sulfate drying, it is concentrated to give dark oil produce product (143.2g, y=73%).
1h nmr(cd3od,500mhz):δppm 8.45(s,1h),8.25(brs,1h),7.98(s,1h),7.61(m,
4h),7.37(s,1h),7.16(s,1h),7.10(m,1h),7.00(m,1h),5.80(s,1h),4.18(m,1h),4.03(m,
1h),3.65(m,2h),3.56(m,1h),3.10(m,1h),3.00(m,1h),2.62(s,3h),2.17-1.92(m,2h),
1.55-1.65(m,4h),1.38(s,9h);Esi/ms:m/z=583 (m+h)+.
Embodiment 4: the preparation of compound 6
By compound 5 (104g, 178.9mmol), methyl alcohol (620ml, 6v) is added in 1l there-necked flask, and temperature control is less than 25 DEG C
Dropping 4m hcl/ ethyl acetate (130ml) solution, reaction overnight, tlc monitoring raw material reaction completely, concentrates, and oil pump draws dry
104g crude product, adds water (900ml), ethyl acetate (1350ml), stirs to system clarification, standing, separates organic layer, aqueous phase is used
Ethyl acetate (500ml) extracts 1 time again, merges organic phase, adds water (180ml), concentrates most of ethyl acetate, to starting
Have solid separate out, ice bath cool down, stirring and crystallizing 30min, filter, filter cake dry after white solid (57.9g, yield 86%, pure
Degree 98.3%).
1h nmr(cd3od,500mhz):δppm 8.45(s,1h),8.25(brs,1h),7.98(s,1h),7.61(m,
4h),7.37(s,1h),7.16(s,1h),7.10(m,1h),7.00(m,1h),4.18(m,1h),4.03(m,1h),3.56(m,
1h),3.10(m,1h),3.00(m,1h),2.62(s,3h);Esi/ms:m/z=398 (m+h)+.
Embodiment 5: the preparation of compound 7
Addition compound 1 (50g, 237mmol, 1eq) in 500ml there-necked flask, triethylamine (72g, 713mmol, 3eq), two
Dimethyl dicarbonate butyl ester (51.7g, 237mmol, 1.0eq), dichloromethane (250ml, 5v), mixture reacts 3 hours at room temperature,
Tlc detection raw material reaction is complete.Add water (500ml) toward reaction system, stir 5 minutes, standing, separate organic phase, aqueous phase is used
Dichloromethane (200ml) extracts 1 time again, merges organic phase, is respectively washed once with saturated aqueous common salt (500ml) and water (500ml), no
Aqueous sodium persulfate is dried, and is concentrated to give black liquor (73g, y=100%).
1h nmr(cdcl3,500mhz):δppm 8.21(s,1h),8.02(s,1h),7.51(s,1h),2.06(s,
3h),1.38(s,9h);Esi/ms:m/z=311 (m+h)+.
Embodiment 6: the preparation of compound 8
In the there-necked flask of 1l, addition compound 7 (52g, 168.8mmol, 1eq), connection boric acid pinacol ester (42.9g,
168.8mmol, 1eq), sodium acid carbonate (14.2g, 168.8mmol, 1eq) and dmso (500ml), stir under nitrogen protection
After 15min, add pd (dppf) cl2(1.38g, 1.7mmol, 0.01eq), is heated to after nitrogen displacement flowing back, reacts 1 hour.
Lcms monitoring raw material reaction is complete, is down to room temperature, adds water (500ml), ethyl acetate (500ml), silica gel (50g), stirs 5 minutes
After filter.Separate organic phase, aqueous phase ethyl acetate (500ml) extracts 1 time again.Merge organic phase, wash one with saturated common salt
Secondary, anhydrous sodium sulfate drying, it is concentrated to give black liquor 60.3g, y=100%).Without purifying, it is directly used in the next step.
1h nmr(cdcl3,500mhz):δppm 8.32(s,1h),8.13(s,1h),7.62(s,1h),2.06(s,
3h),1.38(s,9h),1.25(s,12h);Esi/ms:m/z=359 (m+h)+.
Embodiment 7: the preparation of compound 9
In 3l there-necked flask, add compound 4 (150g, 336mmol, 1eq), compound 8 (120g, 336mmol, 1eq), carbon
Sour sodium (35.6g, 336mmol, 1eq), dioxane (1500ml, 10v), water (150ml, 1v), nitrogen protection is lower to add pd
(dppf)cl2(2.5g, 3.36mmol, 0.01eq), nitrogen displacement, it is warming up to backflow, reacts 1 hour, lcms monitoring raw material is anti-
Should be completely.Add water (1.5l), ethyl acetate (1.5l), silica gel (150g), stir 10min, filter, filtrate separates organic layer,
Aqueous phase is extracted 1 time with ethyl acetate (1.5l), merges organic phase, and organic phase saturated aqueous common salt (1.5l) washes 1 time, anhydrous slufuric acid
Sodium is dried, and is concentrated to give dark oil produce product (122.4g, y=61%).
1h nmr(cd3od,500mhz):δppm 9.0(s,1h),8.38(s,1h),8.25(brs,1h),8.07(m,
2h),7.60-7.63(m,3h),7.32(m,1h),7.18(s,1h),7.11(m,2h),4.48(s,1h),3.81(s,1h),
3.56(m,1h),2.81(m,1h),2.56(m,1h),2.06(s,3h),1.38(s,18h);Esi/ms:m/z=598 (m+h)
+.
Embodiment 8: the preparation of compound 6
By compound 9 (122.4g, 204.7mmol), methyl alcohol (750ml, 6v) is added in 1l there-necked flask, and temperature control is less than 25
The solution of dropping 4m hcl/ ethyl acetate (150ml) at DEG C, ambient temperature overnight is reacted, and tlc monitoring raw material reaction completely, concentrates, oil
Pump draws dry compound 6 crude product, recrystallizes to obtain white solid (66.7g, yield 82%, purity 98.1%).
1h nmr(cd3od,500mhz):δppm 8.45(s,1h),8.25(brs,1h),7.98(s,1h),7.61(m,
4h),7.37(s,1h),7.16(s,1h),7.10(m,1h),7.00(m,1h),4.18(m,1h),4.03(m,1h),3.56(m,
1h),3.10(m,1h),3.00(m,1h),2.62(s,3h);Esi/ms:m/z=398 (m+h)+.
Embodiment 9: the preparation of compound 10
Compound 1 (50g, 238mmol, 1eq), triethylamine (360g, 3.57mol, 15eq), chloromethane is added in 1l there-necked flask
Acid benzyl ester (406g, 2380mmol, 10eq), oxolane (250ml, 5v), slow temperature rising reflux, reacts 3 hours, tlc detects
Raw material reaction is complete.Add the aqueous solution (500ml), the ethyl acetate (300ml) of potassium carbonate toward reaction system, stir 5 minutes, quiet
Put, separate organic phase, aqueous phase ethyl acetate (200ml) extracts 1 time again, merge organic phase, with saturated aqueous common salt (500ml) and
Water (500ml) is respectively washed once, anhydrous sodium sulfate drying, is concentrated to give black liquor (82g, y=100%).
1h nmr(cdcl3,500mhz):δppm 8.21(s,1h),8.02(s,1h),7.51-7.38(m,6h),5.18
(s,2h),2.08(s,3h)ppm;Esi/ms:m/z=345 (m+h)+.
Embodiment 10: the preparation of compound 11
In the there-necked flask of 3l, addition compound 10 (82g, 238mmol, 1eq), connection boric acid pinacol ester (604g,
2380mmol, 10eq), sodium carbonate (252g, 2380mmol, 10eq) and thf (800ml), stir 15min under nitrogen protection
Afterwards, add pd (dppf) cl2(87g, 119mmol, 0.5eq), room temperature reaction 48 hours after nitrogen displacement.Lcms monitoring raw material is anti-
Should be complete, it is down to room temperature, adds water (500ml), ethyl acetate (500ml), silica gel (80g), stirring was filtered after 5 minutes.Separate
Machine phase, aqueous phase ethyl acetate (500ml) extracts 1 time again.Merge organic phase, washed once with saturated common salt, anhydrous sodium sulfate
It is dried, be concentrated to give black liquor 93g, y=100%.Without purifying, it is directly used in the next step.
1h nmr(cdcl3,500mhz):δppm 8.32(s,1h),8.13(s,1h),7.62(s,1h),7.47-7.38
(m,5h),5.18(s,2h),2.06(s,3h),1.25(s,12h)ppm;Esi/ms:m/z=392 (m+h)+.
Embodiment 11: the preparation of compound 12
Toward in 250ml there-necked flask, add compound 4 (10.5g, 23.7mmol, 1eq), compound 11 (93g, 237mmol,
10eq), sodium carbonate (25.1g, 237mmol, 10eq), dioxane (50ml, 5v), water (50ml, 5v), nitrogen protection is lower to be added
pd(dppf)cl2(8.7g, 11.85mmol, 0.5eq), nitrogen displacement, room temperature reaction 48 hours, lcms monitoring raw material reaction is complete
Entirely.Add water (500ml), ethyl acetate (250ml), silica gel (10g), stir 10min, filter, filtrate separates organic layer, aqueous phase
Extracted 1 time with ethyl acetate (250ml), merge organic phase, organic phase saturated aqueous common salt (300ml) washes 1 time, anhydrous sodium sulfate
It is dried, be concentrated to give dark oil produce product (9.4g, y=63%).
1h nmr(cd3od,500mhz):δppm 9.08(s,1h),8.41(s,1h),8.29(brs,1h),8.10(m,
2h), 7.67-7.61 (m, 3h), 7.47-7.32 (m, 6h), 7.19 (s, 1h), 7.10 (m, 2h), 5.18 (s, 2h), 4.52 (s,
1h),3.54(s,1h),3.58(m,1h),2.86(m,1h),2.61(m,1h),2.06(s,3h),1.38(s,9h);esi/ms:
M/z=632 (m+h)+.
Embodiment 12: the preparation of compound 6
By compound 10 (9.4g, 14.9mmol), methyl alcohol (60ml, 6v) is added in 100ml hydrogenation bottle, adds 1g
10%pd/c, under 50psi Hydrogen Vapor Pressure, is stirred at room temperature 2 hours, and tlc monitoring cbz protection is sloughed, and is filtered to remove pd/c, filtrate
Put into 250ml there-necked flask, temperature control drips the solution of 4m hcl/ ethyl acetate (12ml), reaction overnight at being less than 25 DEG C, tlc supervises
Control raw material reaction completely, concentrates, and oil pump draws dry product crude product, recrystallizes to obtain white solid (4.6g, yield 78%, purity
97.9%).
1h nmr(cd3od,500mhz):δppm 8.45(s,1h),8.25(brs,1h),7.98(s,1h),7.61(m,
4h),7.37(s,1h),7.16(s,1h),7.10(m,1h),7.00(m,1h),4.18(m,1h),4.03(m,1h),3.56(m,
1h),3.10(m,1h),3.00(m,1h),2.62(s,3h);Esi/ms:m/z=398 (m+h)+.
The invention provides a kind of synthetic method of atp competitiveness small molecule akt inhibitor a443654, process is simple, always
High income, low production cost, environmentally friendly, suitable large-scale production.
The all documents referring in the present invention are all incorporated as reference in this application, independent just as each document
It is incorporated as with reference to like that.In addition, it is to be understood that after the above-mentioned instruction content having read the present invention, those skilled in the art can
To make various changes or modifications to the present invention, these equivalent form of values equally fall within the model that the application appended claims are limited
Enclose.