CN114478407B - Preparation method and application of chiral homopiperazine and derivatives thereof - Google Patents
Preparation method and application of chiral homopiperazine and derivatives thereof Download PDFInfo
- Publication number
- CN114478407B CN114478407B CN202210077530.0A CN202210077530A CN114478407B CN 114478407 B CN114478407 B CN 114478407B CN 202210077530 A CN202210077530 A CN 202210077530A CN 114478407 B CN114478407 B CN 114478407B
- Authority
- CN
- China
- Prior art keywords
- formula
- chiral
- compound
- homopiperazine
- reaction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/08—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 not condensed with other rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a preparation method and application of chiral homopiperazine and derivatives thereof, wherein p-methoxybenzyl protecting group is introduced at first when reaction is started, then a substitution reaction, mitsunobu cyclization in a molecule and a reaction process of deprotection are carried out to produce a key intermediate, suvorexant can be synthesized through the key intermediate, and 4 chiral isomerism 3, 5-dimethyl-1, 4-diazacycloheptane derivatives are synthesized by utilizing the key intermediate. The raw materials and the auxiliary materials used in the invention are cheap and easy to obtain, the synthetic route is not fear of acid and alkali, and various processes can be used; all intermediates in the route are solid, and can be purified through crystallization operation, so that column chromatography is avoided; the synthesis method has the potential of synthesizing chiral homopiperazine at any position, and the method has the advantages of cheap and easily obtained raw materials, simple operation, high yield, environmental protection and easy industrial amplification.
Description
Technical Field
The invention relates to the fields of organic chemistry and pharmaceutical chemistry, in particular to a preparation method and application of chiral homopiperazine and derivatives thereof.
Background
The chiral homopiperazine and its derivative are important nitrogen-containing heterocyclic medicine intermediates, and the contained double nitrogen atom may react with several organic compounds, and has especially important effect in modifying the structure of chemical medicine, and the medicine synthesized with the intermediates has excellent pharmacological activity and bioactivity, such as antibiotic, anti-inflammatory, antiviral, anticancer, etc. and may be used widely in developing new medicine. Therefore, the development of the synthesis and property research of chiral homopiperazine and derivatives thereof has very important theoretical significance and practical value for developing new medicines.
Suvorexant (suvorexant) with the chemical name 5-chloro-2- [ (5R) -5-methyl-4- [ 5-methyl-2- (2H-1, 2, 3-triazol-2-yl) benzoyl ] -1, 4-diazepan-1-yl ] -1, 3-benzoxazole. The drug was developed by the company moesadong and approved for sale by the FDA in the united states in 2014, and was the first Orexin receptor inhibitor available under the trade name Belsomra. The drug is a dual orexin receptor antagonist and has been approved for the treatment of insomnia, mainly acting on the excitatory neuropeptides of orexin a and B. The structure is present in orexin neurons of the hypothalamus and plays an important role in regulating the sleep-wake cycle, circadian rhythms, energy metabolism, rewarding directional behavior, anxiety-arousal and stress-response.
The structural formula is as follows:
the introduction of chiral homopiperazine ring is the most important link in the synthesis of suvorexant. The chiral homopiperazine ring is introduced into the suvorexant molecular structure, and three main approaches are:
joc,2010,53 (14): 5320-5332A synthetic route is disclosed
The method takes N-tert-butyloxycarbonyl ethylenediamine as a starting material and generates aza-Michael addition reaction with Methyl Vinyl Ketone (MVK) in diethyl ether. However, the key intermediate needs to be subjected to chiral resolution by using a high performance liquid chromatograph, and the total yield is 13.8%, so that the method is not beneficial to industrial production.
Medicinal Chemistry Reviews,2015,50 (32), 419-432 discloses a synthetic route
The method is the first synthetic process route which can be produced in large quantities after the Merck company proposes a drug synthetic route. The route adopts a step-by-step serial connection method and a chiral resolution method, a large amount of chiral impurities can be generated, the steps are complicated, and the total yield is 35.4%, so that the route has a large optimization space.
Organic Letters,2012,14 (13), 3458-3461 discloses a synthetic route
The method adopts 2-amino-4-chlorophenol 2-17 as a starting material in a transaminase catalytic method. The yield of this route is 45% and the ee value is as high as 99%. The synthesis route has the defects that a step-by-step serial connection method is adopted, and strong alkali LHMDS sensitive to water and air is used, so that inconvenience is brought to operation.
Therefore, the chiral purity of the synthetic route of the chiral homopiperazine ring in the prior art is difficult to control, and the intermediate is mostly oily liquid, is difficult to purify and is not suitable for industrial production.
Disclosure of Invention
In order to overcome the problems in the prior art, the invention provides a preparation method of chiral homopiperazine and derivatives thereof.
The technical scheme adopted for solving the technical problems is as follows: a preparation method of chiral homopiperazine and derivatives thereof comprises the following steps:
step 1: introducing p-methoxybenzyl to protect the compound shown in the formula I to obtain a compound shown in the formula II;
wherein R is 1 Is one of methyl and ethyl;
step 2: preparation of Compounds of formula III from Compounds of formula II by reduction
Wherein R is 2 Is one of ethyl and propyl;
step 3: the compound shown in the formula III is subjected to substitution reaction to obtain the compound shown in the formula IV
R 3 Is one of ethyl and propyl, and when R 3 When ethyl, R 2 Is propyl, when R 3 In the case of propyl, R 2 Is ethyl;
step 4: intramolecular Mitsunobu cyclization from the compound of formula I to give the compound of formula V
R 4 ，R 5 Is one of methyl or H;
step 5: removing p-methoxybenzyl protecting group from compound shown in formula V through deprotection reaction to obtain key intermediate shown in formula VI
R 4 ，R 5 Is one of methyl or H.
The preparation method of the chiral homopiperazine and the derivative thereof, wherein the preparation method of the compound shown in the formula 10 in the step 1 comprises the following steps: and mixing the compound shown in the formula 9 with p-methoxybenzyl amine, heating to 100 ℃ under the protection of nitrogen, refluxing, and purifying after the reaction is finished to obtain the product.
The preparation method of the chiral homopiperazine and the derivatives thereof comprises the following preparation method in the step 2: adding red aluminum into a container, adding the compound obtained in the step 1 in batches under the protection of nitrogen, gradually heating to 80 ℃ for reflux after the material is added, and purifying after the reaction is finished to obtain the product.
The preparation method of the chiral homopiperazine and the derivatives thereof, wherein the preparation method of the compound shown in the formula I in the step 3 comprises the following steps: mixing the compound obtained in the step 2, alkanolamine and acetonitrile, protecting with nitrogen, cooling at 0 ℃, and adding the dried K 2 CO 3 The powder is gradually heated to 30 ℃ for reaction, and after the reaction is finished, the product is obtained by purification.
The preparation method of the chiral homopiperazine and the derivative thereof comprises the step of preparing the chiral homopiperazine and the derivative thereof, wherein the alkanolamine is ethanolamine or propanolamine.
The preparation method of the chiral homopiperazine and the derivatives thereof, wherein the preparation method of the compound shown in the formula II in the step 4 is as follows: mixing the compound shown in the formula I obtained in the step 3, diisopropyl azodicarboxylate and tetrahydrofuran, protecting nitrogen, cooling at 0 ℃, adding triphenylphosphine in batches, reacting at 0 ℃ after feeding, and purifying to obtain the product after the reaction is finished.
The preparation method of the chiral homopiperazine and the derivative thereof, wherein the preparation method of the compound shown in the formula III in the step 5 comprises the following steps: the compound shown in the formula II and obtained in the step 4 are subjected to ClCOOCH 2 ClMe and dry toluene are mixed, nitrogen is used for protection, the temperature is raised to 70 ℃ for reflux, when all raw materials are converted into intermediates, the pressure is reduced at 40 ℃, toluene is removed, methanol is added, the temperature is raised to 65 ℃ for reflux, after the reaction is finished, the pressure is reduced at 40 ℃, methanol is removed, and the product is purified.
The preparation method of chiral homopiperazine and derivatives thereof and the application of the products thereof, wherein the key intermediate shown in the formula III obtained in the step 5 can be used for preparing Suvorexant.
The preparation method of chiral homopiperazine and its derivatives and the application of the products thereof, wherein the key intermediate shown in the formula III obtained in the step 5 can be used for synthesizing chiral isomerism 3, 5-dimethyl-1, 4-diazacycloheptane derivatives.
The beneficial effects of the invention are as follows: the raw materials and the auxiliary materials used in the invention are cheap and easy to obtain, the synthetic route is not fear of acid and alkali, and various processes can be used; all intermediates in the route are solid, and can be purified through crystallization operation, so that column chromatography is avoided; the synthesis method has the potential of synthesizing chiral homopiperazine at any position, and the method has the advantages of cheap and easily obtained raw materials, simple operation, high yield, environmental protection and easy industrial amplification.
Drawings
The invention will be further described with reference to the drawings and examples.
FIG. 1 is a synthetic route diagram of key intermediates of the present invention;
FIG. 2 is a hydrogen spectrum of the compound represented by formula 10 of the present invention;
FIG. 3 is a hydrogen spectrum of a compound represented by formula 11 of the present invention;
FIG. 4 is a hydrogen spectrum of a compound represented by formula 12 of the present invention;
FIG. 5 is a hydrogen spectrum of a compound represented by formula 13 of the present invention;
FIG. 6 is a hydrogen spectrum of a compound of formula 14 of the present invention;
FIG. 7 is a hydrogen spectrum of a compound represented by formula 15 of the present invention;
FIG. 8 is a hydrogen spectrum of a compound of formula 16 according to the present invention;
FIG. 9 is a hydrogen spectrum of a compound of formula 17 of the present invention;
FIG. 10 is a hydrogen spectrum of a compound represented by formula 2 of the present invention;
FIG. 11 is a hydrogen spectrum of a compound of formula 18 of the present invention;
FIG. 12 is a hydrogen spectrum of a compound represented by formula 20 of the present invention;
FIG. 13 is a hydrogen spectrum of a compound of formula 21 of the present invention;
FIG. 14 is a hydrogen spectrum of a compound of formula 22 of the present invention;
FIG. 15 is a carbon spectrum of a compound of formula 22 of the present invention;
FIG. 16 is an MS spectrum of a compound represented by formula 22 of the present invention.
Detailed Description
The present invention will be described in detail below with reference to the drawings and detailed description to enable those skilled in the art to better understand the technical scheme of the present invention.
[ example 1 ]
The embodiment discloses a preparation method of chiral homopiperazine and derivatives thereof, a specific synthetic route is shown in fig. 1, and the specific synthetic method comprises the following steps:
(1) The specific process for synthesizing the compound of formula 10 is:
raw material 9 (127.0 g,1075.01mmo 1), PMBNH 2 (139.4 g,1015.83 mmo1) in a 1000ml three-necked flask, N 2 Protecting, gradually heating the oil bath to 100 ℃ and refluxing for 10 hours, after the reaction is finished, adding EA (250 ml), stopping steaming until part of crystals are separated out, adding PE (500 ml), stirring for 30 minutes under ice bath, carrying out suction filtration, washing a filter cake with 100ml of mixed solvent with the volume ratio of EA to PE=1:2 at the temperature of 0 ℃, carrying out vacuum drying at the temperature of 40 ℃ under reduced pressure for 3 hours, and carrying out rotary-vane vacuum pump drying to obtain 170g (887.13 mmo 1) of white powder, wherein the calculated yield is 74%.
The obtained compound of formula 10 was subjected to experiments by nuclear magnetic resonance spectrometer (Bruke model ASCEND 400) to obtain hydrogen spectrum as shown in FIG. 2, and the specific experimental data is 1 H NMR(400MHz,CDCl 3 )δ7.19(d,J＝8.6Hz,2H),6.85(d,J＝8.6Hz,2H),6.16(s,1H),4.36(d,J＝5.6Hz,2H),4.18(ddt,J＝12.2,6.2,3.1Hz,1H),3.79(s,3H),3.76(d,J＝3.1Hz,1H),2.31(qd,J＝15.3,5.9Hz,2H),1.20(d,J＝6.3Hz,3H)。
(2) The specific process for synthesizing the compound of formula 11 is:
red aluminum (280.0 g,1388.5 mmol 1) was added to a 2000ml three-necked flask, N 2 Protecting, adding the compound (50.0 g,223.94mmo 1) of formula 10 obtained in the previous step in batches, gradually heating the oil bath to 80 ℃ and refluxing for 8 hours after the addition, slowly pouring the reaction system into 1kg of ice to quench after the reaction is finished, adding 350ml of NaOH solution (10% alkaline water), extracting with EA (3X 200 ml), washing with 100ml of saturated NaCl solution once, and washing with anhydrous Na 2 SO 4 Drying, concentrating under reduced pressure at 40 ℃, drying by a rotary vane vacuum pump, adding 105g of EA into the obtained crude product, stirring uniformly, slowly introducing HCl gas under ice bath to adjust PH=4-5 to form salt, stirring for 30min, carrying out suction filtration, washing a filter cake with 50ml of EA at 0 ℃, drying the filter cake under reduced pressure for 1h at 40 ℃, adding 100ml of isopropanol into the filter cake, heating to 55-60 ℃ for dissolving, naturally cooling and precipitating, cooling under ice bath, stirring for 30min, carrying out suction filtration, leaching the filter cake with cold 50ml of isopropanol, collecting the filter cake, carrying out vacuum drying on the filter cake under reduced pressure at 40 ℃ for 4h, and drying by a rotary vane vacuum pump to obtain 39.0g (158.74 mmo1) of white powder with the yield of 70.8 percent。
The obtained compound of formula 11 was subjected to experiments by using a nuclear magnetic resonance spectrometer with model number ASCEND 400 of Bruke company, and the obtained hydrogen spectrogram is shown in FIG. 3, and specific experimental data are as follows: 1H NMR (400 MHz, meOD) delta 7.42 (d, J=8.7 Hz, 2H), 7.03-6.96 (m, 2H), 4.88 (s, 4H), 4.21-4.08 (m, 2H), 3.95-3.84 (m, 1H), 3.83 (d, J=10.5 Hz, 3H), 3.21-3.06 (m, 2H), 1.90-1.68 (m, 2H), 1.21 (d, J=6.2 Hz, 3H).
(3) The specific method for synthesizing the compound shown in the formula 12 is as follows:
the compound of formula 11 (80.0 g,325.63mmo 1) obtained in the previous step, ethanolamine (96.22 g,390.75mmo 1) and 500mL of acetonitrile were added to a 1000mL three-necked flask, N 2 Protecting, cooling by 0-5 deg.C in ice-water bath, adding dried K 2 CO 3 Powder (94.15 g,681.26 mmo1), water bath gradually heating to 30 ℃ for reaction for 16h, after the reaction is finished, suction filtration, washing a filter cake with 100ml EA, concentrating filtrate at 30 ℃ under reduced pressure, adding 150g EA, stirring, adding 50g PE, cooling in ice water bath, stirring for 30min, suction filtration, washing the filter cake with 100ml mixed solvent with volume ratio EA at 0 ℃ PE=3:1, collecting the filter cake, drying at 40 ℃ under reduced pressure for 3h, and drying by a rotary-vane vacuum pump to obtain 138.7g (317.02 mmo1) white powder with the yield of 93.8%.
The obtained compound of formula 12 was subjected to experiments by using a nuclear magnetic resonance spectrometer with model number ASCEND 400 of Bruke company, and the obtained hydrogen spectrogram is shown in FIG. 4, and specific experimental data are as follows: 1 H NMR(400MHz,CDCl 3 )δ8.04–8.00(m,1H),7.83–7.78(m,1H),7.72–7.66(m,2H),7.14(d,J＝8.6Hz,2H),6.79(d,J＝8.6Hz,2H),3.78(d,J＝2.8Hz,4H),3.61(d,J＝13.1Hz,1H),3.34(d,J＝13.1Hz,1H),3.10(tq,J＝12.8,6.3Hz,2H),2.70–2.47(m,4H),1.61–1.46(m,2H),1.09(d,J＝6.2Hz,3H)。
(4) The specific method for synthesizing the compound shown in the formula 13 is as follows:
the compound of formula 12 (137.7 g,314.74 mmo1) was initially taken as diisopropyl azodicarboxylate DIAD (82.74 g,409.16 mmo1) and 1400ml of THF were added to a 3000ml three-necked flask, N 2 Protecting, cooling by 0-5 ℃ in ice water bath, and then adding PPh 3 (107.61 g,409.16mmo 1) after the addition of the solutionAfter that, the reaction was carried out in an ice bath for 4 hours. After the reaction, 500ml of 1N hydrochloric acid was added dropwise under ice bath to adjust pH=5 to 6, the mixture was extracted with a volume ratio PE: EA=1:20 (3X 500 ml), the aqueous phase was adjusted to pH=8 to 9 with 500ml of 10% NaOH solution, stirred well, extracted with EA (3X 500 ml), and then extracted with 100ml of saturated NaHCO 3 Washing with solution once, washing with 100ml NaCl solution once, combining organic phases, washing with anhydrous Na 2 SO 4 Drying, concentrating under reduced pressure at 40 ℃, subjecting the obtained yellow oily matter to column chromatography by using a mixed solvent of DCM (MeOH=100:1-10:1), collecting a product, concentrating under reduced pressure at 40 ℃, drying by using a rotary vane vacuum pump, adding 80g of EA, uniformly stirring, adding 40g of PE, crystallizing, stirring for 30min under ice bath, carrying out suction filtration, washing a filter cake by using a mixed solvent of 100ml of EA at 0 ℃ and PE=2:1, collecting the filter cake, drying under reduced pressure at 40 ℃ for 3h, and drying by using a rotary vane vacuum pump to obtain 65.8g (154.47 mmo1) of white powder. The yield thereof was found to be 55.6%.
The obtained compound of formula 13 was subjected to experiments by using a nuclear magnetic resonance spectrometer with model number ASCEND 400 of Bruke company, and the obtained hydrogen spectrum is shown in FIG. 5, and specific experimental data are as follows: 1 H NMR(400MHz,CDCl 3 )δ8.12–7.88(m,1H),7.79–7.50(m,3H),7.17(d,J＝8.6Hz,2H),6.82(d,J＝8.6Hz,2H),4.12(dd,J＝14.3,7.2Hz,2H),3.80(s,3H),3.54–3.39(m,2H),3.31(dd,J＝15.6,11.0Hz,1H),2.91–2.71(m,2H),2.47–2.23(m,2H),1.26(t,J＝7.1Hz,2H),0.96(d,J＝6.4Hz,3H)。
(5) The specific method for synthesizing the compound shown in the formula 14 is as follows:
the compound of formula 13 (10.0 g,23.84mmo 1) obtained in the previous step was reacted with ClCOOCH 2 ClMe (10.22 g,71.52mmo 1), 50ml of dry toluene were added to a 100ml three-necked flask, N 2 And (3) protecting, and heating to 70 ℃ and refluxing for 3 hours. Concentrating under reduced pressure at 40deg.C when all the raw materials are converted into intermediate, removing toluene, adding 40ml of methanol, refluxing at 65deg.C for 1 hr, concentrating under reduced pressure at 40deg.C after reaction, removing methanol, adding 9ml of EA and 12ml of PE, crystallizing, stirring under ice bath for 30min, suction filtering, washing filter cake with mixed solvent with volume ratio of EA: PE=6:1 at 0deg.C 50ml, collecting filter cake, vacuum drying at 40deg.C for 3 hr, and vacuum-drying with rotary vane vacuum pump to obtain 6.77g (22.61 mmo1) of whiteThe yield of the powder was 94.8%.
The obtained compound of formula 14 was subjected to experiments by nuclear magnetic resonance spectrometer (Bruke model ASCEND 400) to obtain hydrogen spectrum as shown in FIG. 6, and the specific data are 1 H NMR(400MHz,MeOD)δ8.17(d,J＝7.6Hz,1H),7.92–7.79(m,3H),4.30–4.19(m,1H),4.06(d,J＝16.8Hz,1H),3.59–3.37(m,3H),3.17(dd,J＝13.7,10.4Hz,1H),3.03(dd,J＝18.7,6.9Hz,1H),2.52–2.39(m,1H),1.81(dt,J＝16.6,10.2Hz,1H),0.97(d,J＝6.5Hz,3H)。
The compound of formula 14 obtained according to the above procedure is an important intermediate for the synthesis of suvorexant, and can be used for the preparation of suvorexant, the specific preparation route and method are as follows:
(6) The specific method for synthesizing the compound shown in the formula 15 is as follows:
the compound of formula 14 (10.0 g,33.40mmo 1) obtained in the previous step, 2, 5-dichlorobenzoxazole (8.38 g,40.08mmo 1) was initially charged with 50ml of DCM in a 250ml three-necked flask, N 2 Protecting, cooling in ice bath, and dripping Et 3 N (10.05 g,100.20mmo 1), at room temperature for 2h, after the end of the reaction, quenched with 30ml of water, extracted with DCM (3X 50 ml), washed once with 50ml of saturated NaCl solution, the organic phases combined, anhydrous Na 2 SO 4 Drying, concentrating under reduced pressure at 40 ℃, drying by a rotary vane vacuum pump, adding 15g of EA, stirring uniformly, adding 18g of PE, crystallizing, cooling under ice bath, stirring for 30min, suction filtering, washing a filter cake by using a mixed solvent with the volume ratio of EA to PE=1:2 at 0 ℃, collecting the filter cake, drying under reduced pressure at 40 ℃ for 3h, and drying by a rotary vane vacuum pump to obtain 13.5g (29.94 mmo 1) of white powdery solid. The yield thereof was found to be 89.6%.
The obtained compound of formula 15 was subjected to experiments by nuclear magnetic resonance spectroscopy (nmr) with model number ASCEND 400 from Bruke corporation, and the obtained hydrogen spectrum is shown in fig. 7, and specific data are: 1 H NMR(400MHz,CDCl 3 )δ8.14–8.01(m,1H),7.77–7.58(m,3H),7.28(d,J＝1.8Hz,1H),7.14(d,J＝8.4Hz,1H),6.97(dd,J＝8.4,2.0Hz,1H),4.26(dd,J＝13.6,6.9Hz,1H),4.13(t,J＝11.8Hz,1H),4.08–3.93(m,2H),3.71–3.50(m,2H),3.50–3.32(m,1H),2.36(dt,J＝14.8,6.0Hz,1H),1.88–1.70(m,1H),1.03(d,J＝6.8Hz,3H)。
(7) The specific method for synthesizing the compound shown in the formula 16 is as follows:
the compound of formula 15 (7.0 g,15.52mmo 1) obtained in the previous step, dodecylmercaptan (12.57 g,62.08mmo 1), K 2 CO 3 (8.58 g,62.08mmo 1), 100ml of acetonitrile was added to a 250ml three-necked flask, N 2 Protecting, heating to 70deg.C, reacting for 16 hr, quenching with 200ml water, extracting with EA (3×50 ml), extracting with 100ml saturated NaHCO 3 Washing with solution once, washing with 100ml saturated NaCl solution once, combining organic phases, anhydrous Na 2 SO 4 Drying, concentrating under reduced pressure at 40 ℃, drying by a rotary vane vacuum pump, adding 4.5g of EA, stirring uniformly, adding 10g of PE, crystallizing, cooling under ice bath, stirring for 30min, suction filtering, washing a filter cake by using a mixed solvent with the volume ratio of EA: PE=5:1 at 0 ℃, collecting the filter cake, drying under reduced pressure at 40 ℃ for 4h, and drying by a rotary vane vacuum pump to obtain 3.7g (13.92 mmo 1) of white powdery solid with the yield of 89.8%.
The obtained compound of formula 16 was subjected to experiments by nuclear magnetic resonance apparatus model ASCEND 400 from Bruke company, and the obtained hydrogen spectrum is shown in fig. 8, and specific data are: 1 H NMR(400MHz,MeOD)δ7.31(d,J＝8.5Hz,1H),7.26(d,J＝2.0Hz,1H),7.04(dd,J＝8.5,2.1Hz,1H),4.08–3.90(m,3H),3.74(ddd,J＝14.5,10.9,3.6Hz,1H),3.53(dt,J＝14.3,4.1Hz,1H),3.43–3.34(m,1H),3.34–3.26(m,1H),2.21–2.10(m,1H),2.03–1.94(m,1H),1.35(d,J＝6.6Hz,3H)。
(8) The specific method for synthesizing the compound Suvorexant shown in the formula 17 comprises the following steps:
the compound (3.7 g,13.92 mmo1), 5-methyl-2- (2H-1, 2, 3-triazol-2-yl) benzoic acid (3.4 g,16.73 mmo1), EDCl (4.6 g,24.00 mmo1), HOBt (2.35 g,17.39 mmo1), et, of the formula 16 obtained in the previous step was first prepared 3 N (3.52 g,34.78mmo 1), 30ml DMF was added to a 100ml three-necked flask, N 2 Protection, reaction at RT for 6h after the end of the reaction, quench with 20ml of water, extract with DCM (3X 30 ml), extract with30ml saturated NaHCO 3 Washing with solution once, washing with 30ml saturated NaCl solution once, combining organic phases, anhydrous Na 2 SO 4 Drying, concentrating under reduced pressure at 40 ℃, drying by a rotary vane vacuum pump, adding 5g of EA, stirring uniformly, adding 5g of n-heptane for crystallization, cooling and stirring for 30min under ice bath, suction filtering, washing a filter cake by using cold 10ml of EA: PE=1:4 mixed solvent, collecting the filter cake, drying under reduced pressure at 40 ℃ for 1h by a rotary vane vacuum pump, adding 4g of EA, stirring and dissolving, adding 4g of n-heptane for crystallization, cooling and stirring for 30min under ice bath, suction filtering, washing the filter cake by using 0 ℃ 5ml of mixed solvent with the volume ratio EA: n-heptane=1:3, collecting the filter cake, drying under reduced pressure at 40 ℃ for 3h by a rotary vane vacuum pump, and obtaining 2.26g (5.01 mmo1) of white powdery solid with the yield of 36.0%.
The obtained compound of formula 17 was subjected to an experiment by a nuclear magnetic resonance spectrometer of model ASCEND 400 from Bruke company, the obtained hydrogen spectrum is shown in figure 9, 1 H NMR(400MHz,CDCl 3 )δ8.06–7.84(m,1H),7.82–7.63(m,2H),7.40–7.23(m,2H),7.13(ddd,J＝22.1,13.5,6.7Hz,2H),7.05–6.92(m,1H),5.13–4.40(m,1H),4.12(ddd,J＝28.6,22.6,11.1Hz,1H),3.98–3.67(m,2H),3.67–3.34(m,1H),3.33–2.99(m,1H),2.68–2.23(m,3H),2.23–1.45(m,2H),1.32–1.12(m,3H),1.02–0.56(m,1H)。
PMB protecting groups are introduced into the whole synthesis route, so that all intermediates in the route are solid, and purification by using a recrystallization method is facilitated.
By using a synthesis method similar to that of example 1,4 new compounds with different chiralities (3, 5-dimethyl-1, 4-chiral homopiperazine) are prepared by selecting raw materials with different chiralities, and the four substances have the potential of synthesizing medicines, and specific synthetic routes and synthetic methods of the four compounds are shown as [ example 2 ] - [ example 5 ].
[ example 2 ]
The specific synthetic route and synthetic method of the (3S, 5R) -tert-butyl-3, 5-dimethyl-1, 4-diazane-1-carboxylic acid ester (namely the compound shown in the formula 22) are as follows:
(1) The specific method for synthesizing the compound shown in the formula 2 is as follows:
l-aminopropanol (30.0 g,399.41mmo 1), pyridine (94.82 g,1198.24mmo 1) were added sequentially to a 1000ml three-necked flask, followed by 300ml DCM, N 2 Protecting, adding NsCl solid (194.8 g,878.70 mmo1) in portions in ice bath, adding at a temperature not higher than 15deg.C, reacting in ice bath for 10min, transferring to room temperature, reacting for 8 hr, cooling in ice bath, adding 500ml 1N HCl dropwise to wash off excessive pyridine, extracting with DCM (100 ml×3) three times, and extracting with 200ml saturated NaHCO 3 Washing with solution once, washing with 200ml saturated NaCl solution once, combining organic phases, anhydrous Na 2 SO 4 Drying, concentrating under reduced pressure at 40 ℃, adding 100g of methanol into the obtained crude product, stirring for crystallization, cooling for 30min under ice bath, suction filtering, washing a filter cake with 50ml of 0 ℃ methanol, collecting the filter cake, drying under reduced pressure at 40 ℃ for 2h, and drying by a rotary vane vacuum pump to obtain 97.8g (375.76 mmo 1) of white powder, wherein the yield is 94.4%.
The obtained compound of formula 2 was subjected to experiments by nuclear magnetic resonance spectrometer (Bruke model ASCEND 400) to obtain hydrogen spectrum as shown in FIG. 10, and the specific data are 1 H NMR(400MHz,CDCl 3 )δ8.30–8.02(m,1H),7.89(dt,J＝6.5,3.0Hz,1H),7.80–7.67(m,2H),5.61(d,J＝6.2Hz,1H),3.88(dd,J＝11.3,5.1Hz,1H),3.53(t,J＝5.7Hz,2H),1.25(d,J＝6.7Hz,3H).melting point:81–83℃。
(2) The specific method for synthesizing the compound shown in the formula 18 is as follows:
the compound of formula 2 (19.92 g,80.69mmo 1), the compound of formula 11 (20.0 g,76.84mmo 1) of example 1, 200ml of acetonitrile were initially introduced into a 250ml three-necked flask, N 2 Protecting, cooling by 0-5 deg.C in ice-water bath, adding dried K 2 CO 3 The powder (21.2 g,153.69mmo 1) was reacted for 8 hours at 20℃in a water bath step by step, after the reaction was completed, the cake was washed with 50ml EA by suction filtration, the filtrate was concentrated under reduced pressure at 30℃and dried by a rotary-vane vacuum pump to give a brown yellow oil. Column chromatography purification [ silica gel: 200-300 meshes and 0.45kg. Dichloro methylAlkane-methanol (100:1-50:1)]The product was collected and concentrated, dried at 40℃in a rotary-vane vacuum pump for 3h to give 30.97g (68.94 mmo 1) of an oil in 90.24% yield.
The obtained compound of formula 18 was subjected to experiments by nuclear magnetic resonance spectroscopy (nmr) with model number ASCEND 400 from Bruke corporation, and the obtained hydrogen spectrum is shown in fig. 11, and specific data are: 1 H NMR(400MHz,CDCl 3 )δ8.09(d,J＝2.7Hz,1H),7.82(s,1H),7.70(d,J＝3.1Hz,2H),7.15(d,J＝7.6Hz,2H),6.83(d,J＝7.4Hz,2H),3.76–3.62(m,3H),3.62–3.49(m,1H),3.19(d,J＝13.0Hz,1H),2.72–2.61(m,1H),2.60–2.50(m,1H),2.49–2.37(m,1H),2.30(dd,J＝13.1,4.2Hz,1H),1.65–1.41(m,2H),1.06(t,J＝6.8Hz,8H)。
(3) The specific method for synthesizing the compound shown in the formula 19 is as follows:
the compound of formula 18 (29.5 g,65.66 mmo1) was first treated with PPh 3 (22.44 g,85.36mmo 1) and 450ml THF were added to a 1000ml three-necked flask, N 2 Protecting, cooling to 0-5 ℃ in ice water bath, slowly dripping DIAD (17.25 g,85.36mmo 1), and reacting for 3h in ice bath after the material feeding is finished. After the reaction is finished, spin-drying the system, adding 80g of EA, stirring to dissolve, dropwise adding 90g of PE, fully stirring, precipitating a large amount of phosphorus triphenyloxide solid, cooling in an ice bath, stirring for 30min, carrying out suction filtration, washing a filter cake with 100ml of EA: PE=1:1 mixed solvent at the temperature of 0 ℃, collecting filtrate, concentrating under reduced pressure at the temperature of 40 ℃, carrying out column chromatography on the obtained yellow oily matter with the mixed solvent of PE: EA=20:1-10:1, collecting a product, concentrating under reduced pressure, carrying out vacuum drying for 3h at the temperature of 40 ℃, and drying by a rotary-vane vacuum pump to obtain 15.33g (35.53 mmo1) of white powder with the yield of 57.6%.
(4) The specific method for synthesizing the compound shown in the formula 20 is as follows:
the compound (14.9 g,17.92mmo 1) represented by the formula 19, clCOOCH 2 ClMe (14.81 g,53.76mmo 1), 75ml of dry acetonitrile were added to a 250ml three-necked flask, N 2 And (3) protecting, and heating to 70 ℃ and refluxing for 2 hours. Concentrating under reduced pressure at 40deg.C when all the raw materials are converted into intermediates, removing acetonitrile, adding 30ml of methanol, refluxing at 60deg.C for 1 hr, concentrating under reduced pressure at 40deg.C after the reaction is completed, removing methanol, adding 15ml of EA, stirring for crystallization, stirring for 30min under ice bath, suction filtering,the filter cake was washed with a mixed solvent of 10ml ea: pe=1:1 at 0 ℃, the filter cake was collected, dried under reduced pressure at 40 ℃ for 3 hours, and dried by rotary-vane vacuum pump to give 9.9g (28.46 mmo 1) of white powder in 82.6% yield.
The obtained compound of formula 20 was subjected to experiments by nuclear magnetic resonance spectroscopy (nmr) with model number ASCEND 400 from Bruke company, and the obtained hydrogen spectrum is shown in fig. 12, and specific data are: 1H NMR (400 MHz, meOD) delta 8.13-8.07 (m, 1H), 7.88-7.82 (m, 2H), 7.81-7.75 (m, 1H), 4.38-4.17 (m, 1H), 4.15-3.89 (m, 1H), 3.62-3.44 (m, 2H), 3.35-3.31 (m, 1H), 3.28 (d, J=2.4 Hz, 1H), 2.47-2.29 (m, 1H), 1.94 (ddd, J=16.3, 9.6,1.5Hz, 1H), 1.50 (d, J=7.1 Hz, 3H), 1.20 (d, J=6.7 Hz, 3H).
(5) The specific method for synthesizing the compound shown in the formula 21 is as follows:
the compound of formula 20 (6.95 g,19.98mmo 1), K was first reacted with 2 CO 3 Powder (4.14 g,29.97mmo 1), 10ml tetrahydrofuran, 10ml water were put into a 100ml three-necked flask, cooled to 0-5℃in an ice-water bath, and then added dropwise (Boc) 2 ) O (4.58 g,20.98mmo 1), after the reaction, naturally heating to room temperature for 2h, separating liquid after the reaction, extracting three times by EA (20 ml multiplied by 3), washing once by 20ml saturated NaCl solution, merging organic phases, and anhydrous Na 2 SO 4 Drying, concentrating under reduced pressure at 40 ℃, and drying by a rotary vane vacuum pump to obtain light yellow oily matter. Column chromatography purification [ silica gel: 200-300 meshes and 0.1kg. DCM pe=1:3]The product was collected and concentrated, and dried at 40℃in a rotary-vane vacuum pump for 4h to give 7.77g (18.89 mmo 1) of an oil in 94.5% yield.
The obtained compound of formula 21 was subjected to experiments by nuclear magnetic resonance spectroscopy (nmr) with model number ASCEND 400 from Bruke corporation, and the obtained hydrogen spectrum is shown in fig. 13, and specific data are: 1 H NMR(400MHz,CDCl 3 )δ8.03(t,J＝8.8Hz,1H),7.71–7.55(m,3H),4.18(dd,J＝8.8,3.6Hz,1H),3.87(ddd,J＝13.9,10.0,3.9Hz,1H),3.81–3.60(m,2H),3.34–3.15(m,2H),2.08–1.89(m,2H),1.53–1.33(m,9H),1.24(dd,J＝10.6,6.0Hz,6H)。
(6) Specific methods for synthesizing the compounds of formula 22 are
The compound of formula 21 (8.22 g,19.98mmo 1), dodecyl mercaptan (1213g,59.94mmo 1), pulled-up K 2 CO 3 Powder (8.28 g,59.94mmo 1), 100ml acetonitrile were added to a 250ml three-necked flask, N 2 And (3) protecting, and raising the temperature to 80 ℃ for reaction for 24 hours. After the reaction, 100ml of water was added for quenching, EA extraction (3X 50 ml) and extraction with 50ml of saturated NaHCO 3 Washing with solution once, washing with 50ml saturated NaCl solution once, combining organic phases, anhydrous Na 2 SO 4 Drying, concentrating under reduced pressure at 40 ℃, and drying by a rotary vane vacuum pump to obtain yellow oily matter. Column chromatography purification [ silica gel: 200-300 meshes and 0.1kg. Dichloromethane, methanol=10:1-5:1]The product was collected and concentrated, dried in a rotary-vane vacuum pump at 40 ℃ for 1h to give an oil, 5ml of acetone and 5ml of n-heptane were added thereto for stirring crystallization, the temperature was lowered and suction filtration was performed, the filter cake was washed with 15ml of acetone: n-heptane=1:2 mixed solvent, the filter cake was collected, and dried in a rotary-vane vacuum pump for 3h to give 0.928g (4.96 mmo 1) of a white solid, yield 24.8%.
The obtained compound of formula 22 was subjected to experiments by nuclear magnetic resonance spectroscopy (nmr) with model number ASCEND 400 from Bruke corporation, and the obtained hydrogen spectrum is shown in fig. 14, and specific data are: 1 H NMR(400MHz,CDCl 3 )δ3.90–3.53(m,2H),3.39–2.83(m,4H),1.81(d,J＝14.3Hz,1H),1.55(d,J＝26.1Hz,1H),1.43(s,9H),1.17–0.89(m,6H). 13 C NMR(101MHz,CDCl 3 ) δ 80.63 (d, j=13.8 Hz), 52.24(s), 50.56(s), 46.52 (d, j=68.9 Hz), 42.83 (d, j=76.2 Hz), 30.56 (d, j=25.5 Hz), 28.34(s), 17.26(s), 14.95(s). Experiments were performed by using a nuclear magnetic resonance apparatus model ASCEND 400 from Bruke corporation, and the obtained carbon spectrum is shown in fig. 15, and specific data are: 13 C NMR(101MHz,CDCl 3 ) δ 80.63 (d, j=13.8 Hz), 52.24(s), 50.56(s), 46.52 (d, j=68.9 Hz), 42.83 (d, j=76.2 Hz), 30.56 (d, j=25.5 Hz), 28.34(s), 17.26(s), 14.95(s). Experiments were performed by a liquid chromatography-mass spectrometer (LC-MS) with the model Dionex Ultimate-300 of Thermo company, and the mass spectrum obtained is shown in FIG. 16, and specific data are as follows: 229.10.
[ example 3 ]
The synthetic route of (3 s,5 s) -tert-butyl-3, 5-dimethyl-1, 4-diazane-1-carboxylate (i.e., the compound shown in formula 23) is specifically as follows:
in this example, the compound represented by formula 11 in example 2 was replaced with the compound represented by formula 26, and the temperature was controlled to-10 ℃ to-5 ℃ in the synthesis of the compound represented by formula 28, so that the reaction effect was good, and the reaction conditions and reagents used in the other synthesis steps were the same as those in example 2.
[ example 4 ]
The synthetic route of (3R, 5R) -tert-butyl-3, 5-dimethyl-1, 4-diazane-1-carboxylate (i.e. the compound shown in formula 24) is specifically as follows:
in this example, the compound represented by formula 2 in example 2 was replaced with the compound represented by formula 31, and the temperature was controlled to-10 ℃ to-5 ℃ in the synthesis of the compound represented by formula 33, so that the reaction effect was good, and the reaction conditions and reagents used in the other synthesis steps were the same as those in example 2.
[ example 5 ]
The specific synthetic route of (3R, 5S) -tert-butyl-3, 5-dimethyl-1, 4-diazane-1-carboxylate (i.e., the compound shown in formula 25) is as follows:
in this example, the compound represented by formula 2 in example 2 was replaced with the compound represented by formula 31, the compound represented by formula 11 was replaced with the compound represented by formula 26, and in the synthesis of the compound represented by formula 37, the reaction temperature was 5℃because of steric hindrance, and the effect of this step on the yield was large, and the reaction conditions and reagents used in the other synthesis steps were the same as those in example 2.
The above embodiments are only exemplary embodiments of the present invention and are not intended to limit the present invention, the scope of which is defined by the claims. Various modifications and equivalent arrangements of this invention will occur to those skilled in the art, and are intended to be within the spirit and scope of the invention.
Claims (6)
1. The preparation method of the chiral homopiperazine and the derivatives thereof is characterized by comprising the following steps:
。
2. the preparation method of the chiral homopiperazine and the derivatives thereof is characterized by comprising the following steps:
。
3. the preparation method of the chiral homopiperazine and the derivatives thereof is characterized by comprising the following steps:
。
4. the preparation method of the chiral homopiperazine and the derivatives thereof is characterized by comprising the following steps:
。
5. the preparation method of the chiral homopiperazine and the derivatives thereof is characterized by comprising the following steps:
。
6. the method for preparing chiral homopiperazine and its derivatives according to claim 1, wherein the method for preparing the compound represented by formula 10 in step 1 is: and mixing the compound shown in the formula 9 with p-methoxybenzyl amine, heating to 100 ℃ under the protection of nitrogen, refluxing, and purifying after the reaction is finished to obtain the product.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210077530.0A CN114478407B (en) | 2022-01-24 | 2022-01-24 | Preparation method and application of chiral homopiperazine and derivatives thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210077530.0A CN114478407B (en) | 2022-01-24 | 2022-01-24 | Preparation method and application of chiral homopiperazine and derivatives thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114478407A CN114478407A (en) | 2022-05-13 |
| CN114478407B true CN114478407B (en) | 2023-08-08 |
Family
ID=81473066
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210077530.0A Active CN114478407B (en) | 2022-01-24 | 2022-01-24 | Preparation method and application of chiral homopiperazine and derivatives thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114478407B (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105367506A (en) * | 2015-12-08 | 2016-03-02 | 华润双鹤药业股份有限公司 | Preparation method of chiral high piperazine ring compound |
| CN106866656A (en) * | 2017-02-28 | 2017-06-20 | 西南交通大学 | One class ergoline derivatives and its purposes in prevention and treatment mental illness |
| CN109912519A (en) * | 2019-03-29 | 2019-06-21 | 成都美域高制药有限公司 | A kind of synthetic method of Su Woleisheng intermediate |
-
2022
- 2022-01-24 CN CN202210077530.0A patent/CN114478407B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105367506A (en) * | 2015-12-08 | 2016-03-02 | 华润双鹤药业股份有限公司 | Preparation method of chiral high piperazine ring compound |
| CN106866656A (en) * | 2017-02-28 | 2017-06-20 | 西南交通大学 | One class ergoline derivatives and its purposes in prevention and treatment mental illness |
| CN109912519A (en) * | 2019-03-29 | 2019-06-21 | 成都美域高制药有限公司 | A kind of synthetic method of Su Woleisheng intermediate |
Non-Patent Citations (1)
| Title |
|---|
| 瑞舒地尔关键中间体的合成工艺改进和优化;陈铖等;《精细化工》;第39卷(第10期);第2155-2160页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN114478407A (en) | 2022-05-13 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP3424899A1 (en) | Sacubitril intermediate and preparation method thereof | |
| CN113214320A (en) | Preparation method of Reidesciclovir compound | |
| EP3814358A1 (en) | Method for preparing 2-indolinospirone compound and intermediate thereof | |
| CN110655517A (en) | Preparation method of doriravir open-loop impurities and impurities thereof | |
| CN114478407B (en) | Preparation method and application of chiral homopiperazine and derivatives thereof | |
| CN101550143B (en) | Industrial compounding method of mule (benzo (e) (1,3) oxazine-2, 4'-piperidine)-4(3H)-ketonic | |
| CN114751849B (en) | Preparation method of brivaracetam and intermediate compound | |
| CN115197153B (en) | Preparation method of 1, 4-diazacycloalkane compound | |
| CN111848546B (en) | 2- (aminomethyl) thiazole-5-nitrile and synthesis method thereof | |
| CN110845512B (en) | Total synthesis method of triterpenoid natural product (+) -Arisugacins F/G | |
| CN107216332A (en) | The synthetic method of (6H) the formic acid base ester of 7 methylol of the tert-butyl group, 7,8 dihydro 4H pyrazolos diazepine 5 | |
| CN109369678B (en) | Synthetic method of natural product isomer (-) -6-epi-Poranteridine | |
| CN108558974B (en) | Preparation and application of sugar-derived nickel pyridine triazole catalyst | |
| CN107129515B (en) | Novel method for synthesizing natural product Cyanolide A analogue | |
| CN107778271B (en) | Synthesis method of anticancer compound CX1409 | |
| US4940803A (en) | Process for synthesis of 1R,2R,5R-2-hydroxy-6-oxo-7-oxabicyclo[3.2.1]-octane | |
| CN117105996B (en) | Preparation method of deoxyribose derivative | |
| CN112142709B (en) | Synthetic method of 6-aryl-2,3,4,5-tetrahydrooxaheptin-3-alcohol derivative | |
| CN115010717B (en) | Full-synthesis preparation method of lycorine (+ -) -alpha-lycorane | |
| CN110218210B (en) | Method for synthesizing moxifloxacin chiral side chain intermediate | |
| CN114736173B (en) | Preparation method of 3- (difluoromethyl) oxetane-3-amine hydrochloride | |
| CN103570781A (en) | Industrialized preparation method for capecitabine | |
| CN116514723A (en) | Synthesis method of 5, 6-2-chloro-1-ethyl-1H-benzimidazole-2-one (DCEBIO) | |
| CN107586280B (en) | Preparation method of plerixafor impurity | |
| CN115260181A (en) | Novel method for synthesizing 5-methylene substituted thiazole-2-amine derivative |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |