CN112300059B - Preparation method of PF-06651600 intermediate - Google Patents
Preparation method of PF-06651600 intermediate Download PDFInfo
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- CN112300059B CN112300059B CN201910679682.6A CN201910679682A CN112300059B CN 112300059 B CN112300059 B CN 112300059B CN 201910679682 A CN201910679682 A CN 201910679682A CN 112300059 B CN112300059 B CN 112300059B
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- 238000002360 preparation method Methods 0.000 title abstract description 18
- 150000001875 compounds Chemical class 0.000 claims abstract description 45
- 238000000034 method Methods 0.000 claims abstract description 25
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 40
- 238000006243 chemical reaction Methods 0.000 claims description 38
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 31
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 28
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 18
- -1 sodium triacetoxyborohydride Chemical compound 0.000 claims description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 13
- 229910021529 ammonia Inorganic materials 0.000 claims description 12
- 239000003638 chemical reducing agent Substances 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 claims description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 239000012279 sodium borohydride Substances 0.000 claims description 8
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- 238000006722 reduction reaction Methods 0.000 claims description 6
- 239000006096 absorbing agent Substances 0.000 claims description 5
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 229910052700 potassium Inorganic materials 0.000 claims description 4
- 239000011591 potassium Substances 0.000 claims description 4
- 239000012321 sodium triacetoxyborohydride Substances 0.000 claims description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 3
- 239000002585 base Substances 0.000 claims description 3
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical group ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 claims description 3
- 229940073608 benzyl chloride Drugs 0.000 claims description 3
- 239000007810 chemical reaction solvent Substances 0.000 claims description 3
- 239000002250 absorbent Substances 0.000 claims description 2
- 230000002745 absorbent Effects 0.000 claims description 2
- 230000001476 alcoholic effect Effects 0.000 claims description 2
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 claims description 2
- 239000002808 molecular sieve Substances 0.000 claims description 2
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims 1
- 235000011114 ammonium hydroxide Nutrition 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 7
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 6
- 230000015572 biosynthetic process Effects 0.000 abstract description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract description 5
- 230000008901 benefit Effects 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 4
- UENBBJXGCWILBM-UHFFFAOYSA-N 6-methylpyridin-3-amine Chemical compound CC1=CC=C(N)C=N1 UENBBJXGCWILBM-UHFFFAOYSA-N 0.000 abstract description 3
- 150000002466 imines Chemical class 0.000 abstract description 2
- 150000002576 ketones Chemical class 0.000 abstract description 2
- 238000005956 quaternization reaction Methods 0.000 abstract description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 235000019441 ethanol Nutrition 0.000 description 7
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 238000004809 thin layer chromatography Methods 0.000 description 6
- 239000000203 mixture Substances 0.000 description 5
- 230000035484 reaction time Effects 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 208000004631 alopecia areata Diseases 0.000 description 4
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 125000001309 chloro group Chemical group Cl* 0.000 description 3
- 230000001276 controlling effect Effects 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000000967 suction filtration Methods 0.000 description 3
- KZOQTVBEJPFESD-UHFFFAOYSA-N 1-benzyl-6-methylpiperidin-3-one Chemical compound CC1CCC(=O)CN1CC1=CC=CC=C1 KZOQTVBEJPFESD-UHFFFAOYSA-N 0.000 description 2
- 201000004384 Alopecia Diseases 0.000 description 2
- 206010009900 Colitis ulcerative Diseases 0.000 description 2
- 208000011231 Crohn disease Diseases 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 201000006704 Ulcerative Colitis Diseases 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 125000001246 bromo group Chemical group Br* 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 230000003676 hair loss Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 101000934996 Homo sapiens Tyrosine-protein kinase JAK3 Proteins 0.000 description 1
- 229940124639 Selective inhibitor Drugs 0.000 description 1
- 102100025387 Tyrosine-protein kinase JAK3 Human genes 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 210000003780 hair follicle Anatomy 0.000 description 1
- 208000024963 hair loss Diseases 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/56—Nitrogen atoms
Abstract
The invention relates to a preparation method of a PF-06651600 intermediate, belonging to the field of pharmaceutical chemistry. The method can take 3-amino-6-methylpyridine as a raw material, and obtain a target compound through amino protection, quaternization, reduction, ketone formation, imine formation, reduction and amino protection. The method has the advantages of mild condition, easily obtained reagent, high product purity, high yield and safe operation, and can be used for industrial production.
Description
Technical Field
The invention relates to the field of pharmaceutical chemistry, in particular to a preparation method of a PF-06651600 intermediate.
Background
Alopecia areata is an autoimmune disease that is primarily characterized by the loss of hair throughout the head, face, and body. The symptoms are caused by the attack of the patient's immune cells on the autologous hair follicles, primarily circular local hair loss. Alopecia areata has an average age of between 25 and 35 years, but can also affect children and adolescents and can occur in both men and women and all ethnicities.
PF-06651600 is a potent, selective inhibitor of JAK3 and has previously been identified as a breakthrough therapy in the FDA for the treatment of alopecia areata. Currently, it is subjected to a phase 3 clinical trial for the treatment of moderate to severe alopecia areata, while continuing the trial for the treatment of Rheumatoid Arthritis (RA), crohn's Disease (CD) and Ulcerative Colitis (UC); the structure of PF-06651600 is shown in the following formula:
the 6-methyl-3-carbamic acid tert-butyl ester-1-benzyl piperidine is an important intermediate for the synthesis of PF-06651600 compounds, which requires the use of expensive metals for the preparation of the intermediate, as disclosed in WO2010048012 for the reduction of pyridine rings to piperidine rings using rhodium metal catalysts; w (W)O2016112298 discloses the use of PtO 2 The pyridine ring is reduced as a catalyst. However, metal catalysts are expensive, generally reduced with hydrogen, heated and hydrogenated at high pressure for a long period of time, and the reaction conditions are severe. For example, ptO is used 2 The platinum black produced is flammable and dangerous to produce. In the prior art, the steps need column chromatography purification, and the large-scale production is difficult.
Therefore, there is an urgent need to research a new method for preparing an intermediate of PF-06651600 to obtain a method that is easy to operate, easy to implement, high in yield, high in purity, low in cost, and environmentally friendly.
Disclosure of Invention
The invention provides a preparation method of a PF-06651600 intermediate.
In one aspect, the present invention provides a process for preparing intermediate compound (g). A process for preparing compound (g),
the method comprises the steps of reacting a compound (e) with ammonia in a reaction solvent in the presence of a water absorbing agent, then adding a reducing agent for reduction reaction, and carrying out post-treatment to obtain a compound (g). The preparation method can reduce the water content in the reaction system, and is beneficial to obtaining higher yield; the reaction condition is mild, the operation is controllable and safe, and the method can be used for industrial production.
In some embodiments, the solvent is at least one of tetrahydrofuran, methanol, ethanol, and acetonitrile; or the solvent is tetrahydrofuran. The method has mild condition and easily obtained reagent.
In some embodiments, the water absorbing agent is at least one of titanium tetraisopropoxide, anhydrous sodium sulfate, and a molecular sieve; or the water absorbing agent is titanium tetraisopropoxide. The water absorbent can reduce the water content in the reaction system, which is beneficial to obtaining higher yield.
In some embodiments, the ammonia is ammonia gas or an alcoholic solution of ammonia; or the ammonia is methanol solution of ammonia or ethanol solution of ammonia.
In some embodiments, the reducing agent is at least one of sodium borohydride, potassium borohydride, and sodium triacetoxyborohydride; alternatively, the reducing agent is sodium borohydride. The addition of the reducing agent is favorable for better reaction, and the high-yield and high-purity product is obtained.
In some embodiments, titanium tetraisopropoxide is added, stirred for 0.5 hour to 1.5 hours, ammonia in methanol solution is added dropwise, stirred for 1 hour to 3 hours with heat preservation, and NaBH is added in small amounts in multiple batches 4 (sodium borohydride) and the reaction is kept for 0.5 to 2 hours.
In one aspect, a process for preparing compound (e) comprises,
the compound (d) is reacted in the presence of concentrated hydrochloric acid and acetic acid to produce the compound (e). The method can better prepare and obtain the compound (e).
In some embodiments, the volume ratio of concentrated hydrochloric acid to acetic acid is 2:1. The reaction conditions are advantageous for obtaining the compound (e) in high yield and purity.
In some embodiments, the temperature of the reaction is from 40 ℃ to 100 ℃; or the reaction temperature is 60-80 ℃. Or the reaction temperature was 70 ℃. The reaction condition is mild, the operation is controllable and safe.
In some embodiments, the reaction time of the reaction is from 3 hours to 8 hours; or the reaction time of the reaction is 4 hours to 6 hours.
In one aspect, a process for preparing compound (d) comprises,
reducing the compound (c) in a solvent at a certain reaction temperature by a reducing agent to generate a compound (d); wherein X is halogen; or X is chlorine; or X is bromine.
The method can better prepare the compound (d), has mild reaction conditions, controllable operation, safety and easy reagent acquisition.
In some embodiments, the solvent is at least one of methanol, ethanol, tetrahydrofuran, and acetonitrile; or the solvent is methanol.
In some embodiments, the reaction temperature is from-10 ℃ to 10 ℃; or the reaction temperature is-5 ℃; or the reaction temperature is-5 ℃.
In some embodiments, the reducing agent is at least one of sodium borohydride, potassium borohydride, and sodium triacetoxyborohydride; or the reducing agent is sodium borohydride.
In some embodiments, the reaction time of the reaction is from 1 hour to 4 hours; or the reaction time of the reaction is 2 hours to 3 hours.
In one aspect, a process for preparing compound (c) comprises,
reacting the compound (b) with benzyl halide in a solvent in the presence of a base to produce a compound (c); wherein X is halogen; or X is chlorine; or X is bromine.
In some embodiments, the solvent is at least one of tetrahydrofuran, toluene, acetonitrile, and ethanol; or the solvent is absolute ethyl alcohol.
In some embodiments, the base is aqueous ammonia.
In some embodiments, the benzyl halide is benzyl chloride or benzyl bromide.
In some embodiments, a method of preparing compound (g) comprises,
in a reaction solvent, in the presence of a water absorbing agent, the compound (e) reacts with ammonia to generate an intermediate compound (f), and then a reducing agent is added for reduction reaction, and after-treatment, the compound (g) is prepared. The preparation method can better control the reaction process and obtain higher yield.
On one hand, the invention provides a preparation method of PF-06651600 intermediate compound (h),
comprising, dropwise adding Boc anhydride (1.1 eq-2.0 eq) into the compound (g) under the condition of taking ethanol as a solvent, wherein the reaction temperature is 10-40 ℃, and performing amino protection reaction to generate the compound (h).
The preparation method of the PF-06651600 intermediate provided by the invention has the advantages of mild conditions, easily obtained reagents, high product purity, high yield and safe operation, and can be used for industrial production.
In some embodiments, a process for preparing a PF-06651600 intermediate is provided in the following reaction scheme:
the preparation method of the PF-06651600 intermediate provided by the invention can take 3-amino-6-methylpyridine as a raw material, and obtains a target compound through amino protection, quaternization, reduction, ketone formation, imine formation, reduction and amino protection, and is a novel method for efficiently preparing the key intermediate 6-methyl-3-carbamic acid tert-butyl ester-1-benzyl piperidine of PF-06651600, which has the advantages of mild condition, easily obtained reagent, high product purity, high yield and safe operation, and is suitable for industrial production.
In the description of the present invention, the meaning of "a plurality" is two or more, unless explicitly defined otherwise.
In the description of the present specification, the descriptions of the terms "some implementations," "some embodiments," "examples," "particular examples," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present invention. In this specification, schematic representations of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, the different embodiments or examples described in this specification and the features of the different embodiments or examples may be combined and combined by those skilled in the art without contradiction.
In the present invention, the expressions "compound (a)" and "compound represented by formula (a)" mean the same compound.
Detailed Description
In order to better understand the technical solution of the present invention, the following further discloses some non-limiting examples, which are further described in detail.
The reagents used in the present invention are all commercially available or can be prepared by the methods described herein.
In the present invention, mmol means millimoles, h means hours, g means grams, ml means milliliters, THF means tetrahydrofuran, meOH means methanol, etOH means ethanol, CH 3 CN represents acetonitrile, DCM represents dichloromethane, EA represents ethyl acetate, boc 2 O represents di-tert-butyl dicarbonate, TLC represents thin-layer chromatography, naBH 4 Sodium borohydride and sodium hydroxide are shown, respectively, with NaOH.
EXAMPLE 1 preparation of N-Boc-3-amino-6-methylpyridine (Compound (b))
21.6g (1.0 eq,200 mmol) of 3-amino-6-methylpyridine, 200ml EtOH are added in sequence to a 500ml single-necked flask, the solution is stirred and cooled to-5℃and 57g (1.3 eq,260 mmol) of Boc are slowly added dropwise 2 O (1.5 eq), after the completion of the dropwise addition, the mixture was stirred at room temperature for about 1 hour, the reaction was transferred to room temperature and stirred overnight, TLC control, developer EA: cyclohexane = 2:1. after the raw materials are reacted, the temperature is raised to 40 ℃ and reduced pressure is evaporated to viscous oily matter in a rotary way, 200ml of water is added for stirring for 2 hours, suction filtration is carried out, and the obtained solid is dried for 24 hours under the vacuum condition of 55 ℃ to obtain 37.4g of off-white solid product with the purity of 97 percent and the yield of 90 percent. LC-MS: M/z (ESI): 209.25 (M+H) + .
EXAMPLE 2 preparation of N-Boc-3-amino-6-methylbenzylpyridine chloride (Compound (c))
To a 500ml single vial was added 22.09g (1.0 eq,106.1 mmol) of N-Boc-3-amino-6-methylpyridine and 220ml of absolute ethanol, and aqueous ammonia was added to adjust the pH to 8-9. Stirring and dissolving at room temperature (25 ℃) until the mixture is clear to obtain yellow clear liquid, adding 26.86g (2.0 eq,212.2 mmol) of benzyl chloride into the reaction, continuing to react at room temperature for 30min, heating to 75 ℃, controlling the reaction for 5h, and controlling the reaction in TLC, and developing the methanol: dcm=1: 10, transferring the raw materials to 0 ℃ after reaction, precipitating white solid, carrying out suction filtration, concentrating the filtrate at 35-40 ℃ under reduced pressure, adding 220ml of ethyl acetate, stirring for 2h at room temperature (20-30 ℃), carrying out suction filtration, and drying at 50 ℃ in vacuum for 20h to obtain 28.4g of off-white solid with the purity of 95% and the yield of 80%. LC-MS: M/z (ESI): 300.1 (M-Cl) - ) + .
EXAMPLE 3 preparation of N-Boc-3-amino-6-methylbenzyl-1, 2,5, 6-tetrahydropyridine (Compound (d))
Preparation of 0.1mol/L NaOH solution: 4g NaOH is dissolved in 1000ml water and stirred to be dissolved to be clear for later use.
Into a 1000ml four-necked flask, 23.48g (1.0 eq,70.1 mmol) of N-Boc-3-amino-6-methylbenzylpyridine chloride and 200ml of methanol were added, and the mixture was dissolved by stirring at room temperature (25 ℃ C.), cooled to-5 ℃ C., 5.84g (2.2 eq,154 mmol) of NaBH 4 Dissolved in 80mL of 0.1N NaOH solution and then slowly added dropwise to a 1000mL four-necked flaskAfter the dripping is finished, the system has solid precipitation, the temperature is raised to 0 ℃ for 2 hours, TLC is controlled, and the developing agent methanol: dcm=1: 10, after the raw materials are reacted, 400ml of water is added for quenching, the mixture is stirred for 0.5h at room temperature, the mixture is filtered by suction, the filter cake is leached three times by 30ml of water, and the white solid is obtained by drying at 55 ℃ for 24h, and the white solid with the purity of 19.7g is obtained>90% yield 93%. LC-MS: M/z (ESI): 303.3 (M+H) + .
EXAMPLE 4 preparation of 6-methyl-1-benzyl-3-piperidone (Compound (e))
To a 100mL single flask, 10g (1.0 eq,33 mmol) of N-Boc-3-amino-6-methylbenzyl-1, 2,5, 6-tetrahydropyridine was added, the temperature was lowered to 0℃and 10mL of a mixed solution of concentrated hydrochloric acid and acetic acid was added, stirred for 15min, then the temperature was raised to 70℃and reacted for 5h, the starting material was reacted, the temperature was lowered to 0℃and 25mL of saturated Na was used 2 CO 3 The pH value of the solution is regulated to be neutral to alkalescence, then 20ml of acetonitrile is added for extraction twice, anhydrous sodium sulfate is dried, the solution is distilled to dryness under reduced pressure at 30 ℃ to obtain brown yellow oily matter, the yield is 100 percent, and the purity is high>90%. The oil was used directly in the next reaction. LC-MS: M/z (ESI): 204.3 (M+H) + .
EXAMPLE 5 preparation of 6-methyl-3-amino-1-benzylpiperidine (Compound (g))
To a 250mL single-necked flask containing 6-methyl-1-benzyl-3-piperidone oil was added 10mL of THF, stirred and dissolved, cooled to 0deg.C, 11.3g (1.2 eq,40 mmol) of titanium tetraisopropoxide (1.5 eq) was added, stirred for 0.5h, 5mL of ammonia in methanol was added dropwise, stirred for 2h with a small amount of NaBH added in multiple portions 4 (1.01 eq,33.3 mmol), incubating for 1h, controlling the reaction time to be complete every 0.5h, adding 20ml saturated NH 4 The Cl solution was quenched, extracted twice with 20ml of dichloromethane and the dichloromethane was distilled off under reduced pressure at 25.+ -. 5 ℃ to give 5.4g of yellow oil in 80% yield and 96% purity. Oil (oil)The material was used directly in the next reaction. LC-MS: M/z (ESI): 205.3 (M+H) +
EXAMPLE 6 preparation of N-Boc-3-amino-6-methyl-1-benzylpiperidine (Compound (h))
To a 100mL single-necked flask containing 5.4g (1.0 eq,26.4 mmol) of 6-methyl-3-amino-1-benzylpiperidine was added 25mL of ethanol and dissolved therein with stirring, the temperature was lowered to 0℃and 6.92g (1.2 eq,31.7 mmol) of Boc was slowly added dropwise 2 O, after the completion of the dropwise addition, was stirred for 0.5h with heat preservation, the reaction was transferred to room temperature and stirred overnight, TLC was controlled, methanol: dcm=1: 10, after the raw materials are reacted, the raw materials are distilled to dryness under reduced pressure at 40 ℃,20ml of ethyl acetate is added for dissolution, 20ml of water is used for washing twice, liquid separation and reduced pressure at 40 ℃ are carried out for spin drying to obtain 6.84g of pale yellow oily substance, the yield is 85.0%, and the purity is 97%. LC-MS: M/z (ESI): 305.3 (M+H) +1 H NMR(400MHz,CDCl 3 )δ7.39–7.29(m,4H),7.28–7.19(m,1H),5.18(s,1H),4.03(d,J＝13.5Hz,1H),3.73(s,1H),3.17(d,J＝13.4Hz,1H),2.63(d,J＝10.5Hz,1H),2.35(s,1H),2.19(d,J＝11.5Hz,1H),1.74(s,2H),1.63–1.52(m,2H),1.44(s,9H),1.18(d,J＝6.0Hz,3H).
While the methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations and combinations of the methods and applications described herein can be made and applied within the spirit and scope of the invention. Those skilled in the art can, with the benefit of this disclosure, suitably modify the process parameters to achieve this. It is expressly noted that all such similar substitutions and modifications will be apparent to those skilled in the art, and are deemed to be included within the present invention.
Claims (10)
1. A process for producing compound (g) which comprises reacting compound (e) with ammonia in the presence of a water absorbing agent in a reaction solvent, then adding a reducing agent for a reduction reaction, and carrying out a post-treatment to produce compound (g), wherein the solvent for the reaction is at least one of tetrahydrofuran, toluene, methanol, acetonitrile and ethanol;
the water absorbent is at least one of titanium tetraisopropoxide, anhydrous sodium sulfate and a molecular sieve;
the reducing agent is at least one of sodium borohydride, potassium borohydride and sodium triacetoxyborohydride.
2. The method of claim 1, wherein the ammonia is ammonia gas or an alcoholic solution of ammonia.
3. The method according to claim 1,
wherein the compound (e) is produced by reacting the compound (d) in the presence of concentrated hydrochloric acid and acetic acid.
4. A process according to claim 3, wherein the volume ratio of concentrated hydrochloric acid to acetic acid is 2:1.
5. A process according to claim 3, wherein the temperature of the reaction of compound (d) is from 40 ℃ to 100 ℃.
6. The process of claim 3, wherein the compound (d) is produced by reducing the compound (c) in a solvent at a reaction temperature by a reducing agent
Wherein X is halogen;
the reducing agent is at least one of sodium borohydride, potassium borohydride and sodium triacetoxyborohydride.
7. The process of claim 6, wherein the reaction temperature of the reaction of compound (c) is-10℃to 10 ℃.
8. The process according to claim 6, wherein the compound (c) is produced by reacting the compound (b) with a benzyl halide in a solvent in the presence of a base
Wherein X is halogen; the alkali is ammonia water.
9. The process of claim 8, the benzyl halide is benzyl chloride or benzyl bromide.
10. The method of claim 6 or 8, wherein the solvent of the reaction is at least one of tetrahydrofuran, toluene, methanol, acetonitrile, and ethanol.
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| CN104974163A (en) * | 2014-04-14 | 2015-10-14 | 广东东阳光药业有限公司 | Substituted heteroaryl compound, composition thereof, and applications thereof |
| CN109761884A (en) * | 2019-01-30 | 2019-05-17 | 湖北扬信医药科技有限公司 | A kind of preparation method and applications of Chiral Amine B |
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